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What are 503B Outsourcing Facilities?

503B outsourcing facilities are registered with the FDA to manufacture compounded medications in large bulk volumes to ship for office use and can also dispense patient-specific prescriptions. Most compounding pharmacies that we’re familiar with are 503As, which means they can make small batches, patient-specific only. If you’re in a field where you’re doing anything office use (administering office injections, IV’s, things of that nature; or looking for the best price point), then working with a 503B is beneficial. 503Bs are beholden to the higher standards of current Good Manufacturing Practices (cGMP) just like Big Pharma. They have more stringent testing for potency and sterility, but medications and products can also be made in large batches, so they become more cost effective. Most of the cost involved with medications is in the labor and testing. Based on economies of scale the more medications the pharmacy can make the more cost effective each unit becomes.

Here are some examples of why it’s important to build a relationship with a 503B outsourcing facility when you are practicing this type of medicine. Establishing a relationship with a licensed compounding pharmacy is important for physicians who need access to hormones, PDE-5 inhibitors, penile injections, gonadotropins, and other specialty medications often prescribed for testosterone therapy in sexual medicine. The reason for this is that some of these medications aren’t available commercially, are often on back order, or most importantly, are very expensive. For example, as most of us know, PDE-5 inhibitors like Viagra run anywhere between $65 to $73 per 100 mg tablet, whereas a compounded generic can cost between $4 and $6, roughly 5-10% of the cost.

503B outsourcing facilities are registered with the FDA to manufacture custom injectable medications in large quantities to ship directly to clinics and hospitals for office use. That’s something that regular compounders cannot do. 503Bs use raw materials sourced from FDA-approved suppliers, the same suppliers that commercial manufacturers use. 503Bs can manufacture large quantities to offer catalog medications at a very low price. Very few 503B outsourcing facilities specialize in testosterone and ED medications. A lot of them focus on the whole purpose of a 503B to fill a niche that commercial manufacturers don’t fill, primarily the IV bags used in hospitals.

At least one pharmacy is licensed in all 50 states to provide both patient-specific and bulk medications for clinic administration, which is important especially if you have multiple locations where you are treating patients across state lines. Of course, adhering to cGMP and USP guidelines is important to always guarantee that the product is sterile and potent for the duration of the shelf life if it’s properly stored. Being able to work with a compounding pharmacy often results in better patient care, because the compounding pharmacies tend to bring back the triad of care that’s missing with the communication between the pharmacist, the patient, and the doctor. Since these medications are often customized, compounding pharmacists have a good relationship with the physicians and communicate very well with them. In turn, they also communicate very well with the patient. That’s something that often gets lost in retail pharmacies.

Here are some of the medications commonly prescribed by physicians and made at a 503B facility within the integrative sexual medicine realm: Injectable testosterone, transdermal testosterone, and other hormones as well; subdermal testosterone pellets, as well as other hormones like progesterone and estradiol; lyophilized gonadotropins for fertility or as an adjunct to testosterone therapy; aromatase inhibitors for estrogen control and SERMS, which are another hormonal agent to stimulate the hypothalamus-pituitary axis. Then into the ED and sexual dysfunction medications; PDE-5 inhibitors, Tri-Mix, etc. Several compounding pharmacies have a whole line of ICI medications; Bi-Mix, Tri-Mix, Quad-Mix and some formulas in between.

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Synergistic Formulas for Hair Growth

As we all know, there are two FDA-approved treatments for hair loss right now, finasteride and minoxidil. There are a lot of problems reported with the use of finasteride for the prevention or reversal of hair loss. In fact, there is a whole forum now for men that are suffering from something called ‘post-finasteride syndrome’. Men that have gone on finasteride or Propecia for many years to halt their hair loss, which has lowered their dihydrotestosterone levels. DHT is responsible for accelerating hair loss. The problem is that DHT is also responsible for sexual energy, libido, rigidity, muscle mass, body fat, metabolism, and things like that; so, when you drop it too low, you might have a full head of hair, but you are not going to be able to optimally function sexually.

What a lot of these men have unfortunately found is that even if they get on testosterone replacement therapy, their DHT levels remain low. Even if they get their DHT levels up into a normal range, they remain unresponsive. We don’t know what happens to cause post-finasteride syndrome, but it’s terrible for the men that suffer because there’s very little that you can do except give them a high level of testosterone and some DHT analogs to try to augment their androgen levels a little bit. Finasteride is not the best form of treatment for hair loss. There are several lawsuits pending right now for men that are suffering from finasteride syndrome. Of course, we know minoxidil, which is Rogaine, is available in some doses OTC. It’s marginally effective. Some are more effective than others, which depends on the type of hair loss, but it’s not very effective as a single treatment.

Now let us review the compounded hair products that are available and have shown to be effective for the treatment of alopecia when applied directly to the scalp. There are compounded formulas that combine FDA-approved medications and alternative therapies, creating a custom product designed to treat, prevent, and reverse hair thinning and loss due to androgenic alopecia.

One of the ingredients is latanoprost. There have been some studies on latanoprost and the effectiveness of growing and thickening hair that’s being lost. A lot of us are familiar with Latisse, which is bimatoprost; also, related to latanoprost to increase length and thickness of eyelashes. It was originally a glaucoma drug which was then found that if you drop it on the eyelashes, they grow very thick and long. It cleared the FDA and became a medication called Latisse. There is latanoprost, which is the same efficacy as bimatoprost. There have been some studies that have specifically used topically applied latanoprost on scalp hair. It not only helped growing hair but it also helped thickening existing hair, which of course, really helps fill in some of the gaps of thinning hair. We have seen this option prescribed now since 2007 and have seen nothing but good feedback. You do have to be consistent with taking it.

Ketoconazole, some of us are familiar with. It’s an antifungal medication that has shown to block DHT in the scalp, so that’s another useful medication.
Spiranolactone, which is a diuretic prescribed for edema. It’s also prescribed for female pattern baldness. Women cannot use finasteride because it would completely shut down their testosterone and affect their endocrine system. Truthfully, men shouldn’t take it either but spironolactone is a very mild androgen blocker, so it’s not like finasteride where DHT is blocked completely. It will block some of the receptor sites and lower the androgen level, so if a female is suffering from pattern baldness due to excessive androgens, spironolactone can be a very conservative therapy to block those excess androgens. Of course, it also applies to acne. It has been prescribed for females with acne, and men as well. The problem with giving men spironolactone is that it can lower their testosterone.

Azelaic acid is another naturally occurring substance that has also been shown to inhibit 5-alpha-reductase in human skin when applied topically, so this is another DHT blocker that doesn’t become systemic like finasteride, and can possibly lower hormone levels.

One company created a line of products called Andro-Block. There are different formulas depending on what you want to do, but basically, these formulas are combined with these ingredients we just discussed into a single solution depending on what the goal is. They offer a line of custom compounded scalp solutions for hair restoration. Andro-Block products contain these combined ingredients in a single solution designed for specific goals. There are multiple formulas available to allow for treatment and customization.

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Compounded PDE-5 inhibitor Basics

Phosphodiesterase-Type 5 Inhibitors Mechanism:
During sexual arousal, nitric oxide (NO) is released from nerve terminals and endothelial cells in the corpus cavernosum. NO activates guanylate cyclase to convert guanosine triphosphate (GTP) into cyclic guanosine monophosphate (cGMP), triggering a cGMP-dependent cascade of events. The accumulation of cGMP leads to smooth-muscle relaxation in the corpus cavernosum and increased blood flow to the penis. PDE5 is an enzyme found primarily in the smooth muscle of the corpus cavernosum that selectively cleaves and degrades cGMP to 5′-GMP. PDE5 inhibitors are similar in structure to cGMP; they competitively bind to PDE5 and inhibit cGMP hydrolysis, thus enhancing the effects of NO. This increase in cGMP in the smooth muscle cells is responsible for prolonging an erection. PDE5 inhibitors lack a direct effect on corpus cavernosum smooth-muscle relaxation. Therefore, after administration, adequate sexual stimulation is necessary for an erection to occur.

PDE-5 Inhibitor Products:
Sildenafil was the first PDE5 inhibitor to arrive on the market, in 1998. The usual dose of sildenafil is 50 mg (25 to 100 mg) taken one hour before sexual activity. The effects of sildenafil last for approximately four hours, and patients should be instructed to use no more than one dose within 24 hours. Fatty meals reduce the absorption of sildenafil; therefore, the drug should be taken on an empty stomach.

Vardenafil (Levitra), the first second-generation PDE5 inhibitor to be developed, is given at a usual dose of 10 mg (2.5 to 20 mg) one hour before sexual activity. Elderly patients and those with moderate liver dysfunction should receive a lower initial dose of 5 mg. Vardenafil begins working within 30 to 45 minutes after administration and lasts for about four hours. As with sildenafil, patients taking vardenafil should not use more than one dose within a 24-hour period. Patients should not take vardenafil within three hours of fatty meals, due to a reduction in absorption.

The newest PDE5 inhibitor is tadalafil (Cialis), which has a longer duration of action–approximately 36 hours–than sildenafil or vardenafil. In addition, the usual dose of 10 mg (5 to 20 mg) should be taken about 30 minutes before sexual activity–possibly allowing patients more opportunity for spontaneity. Food intake does not appear to affect the absorption of tadalafil; thus, the drug may be taken without regard to meals.

Though considered generally safe for most patients, including those taking multiple antihypertensives, PDE5 inhibitors are not a viable treatment option for every man with ED. Patients with a cardiovascular history that includes a recent myocardial infarction or stroke (within the past two weeks), cerebral vascular accident, life-threatening arrhythmia, hypertension (blood pressure >170/100 mmHg), hypotension (blood pressure <90/50 mmHg), unstable angina, and/or moderate to severe heart failure (New York Heart Association class III or IV) should not receive therapy with these agents. The risks and benefits associated with PDE5 inhibitor therapy and the patient’s medical history must be assessed.

Because PDE5 is inhibited in penile tissue as well as extragenital tissue, patients treated with PDE5 inhibitors may experience headache, facial flushing, nasal congestion, dyspepsia, and dizziness. Sildenafil also inhibits PDE type 6 in the retina. Therefore, patients treated with sildenafil may experience sensitivity to light, blurred vision, and loss of blue-green color discrimination, all of which are generally considered reversible. Tadalafil also inhibits PDE type 11 in skeletal tissue, possibly leading to back and muscle pain. Priapism, or painful, prolonged erections, is an extremely rare adverse effect, especially with shorter-acting agents, such as sildenafil and vardenafil. However, patients should be counseled to seek immediate medical attention if they experience erections lasting longer than four hours. PDE5 inhibitors may also cause various cardiovascular effects, including ventricular arrhythmias, cerebrovascular hemorrhages, myocardial infarctions, transient ischemic attacks, hypertension, and even sudden cardiac death. These adverse cardiac effects confirm the importance of a thorough cardiology evaluation in patients with a significant cardiovascular history.

PDE5 inhibitors should never be used in patients who are receiving scheduled or intermittent nitrates, due to a risk for severe hypotension. Organic nitrates supply additional NO, which increases cGMP levels and can lead to hypotension. Interestingly, dietary sources of nitrates and nitrites do not interact with the PDE5 inhibitors, as they do not increase circulating levels of NO. The PDE5 inhibitors are metabolized through the cytochrome P-450 isoenzyme 3A4 (CYP3A4). Therefore, inhibitors of CYP3A4 (e.g., cimetidine, ketoconazole, ritonavir) may prolong the effects of PDE5 inhibitors. Patients receiving such agents may need a lower dose of the PDE5 inhibitor. Alpha-adrenergic antagonists (e.g., terazosin, doxazosin, prazosin) commonly used in the management of benign prostatic hyperplasia (BPH)can cause hypotension, especially when given in combination with PDE5 inhibitors. For patients receiving more than 25 mg of sildenafil, the dose of the alpha-antagonist and sildenafil should be separated by at least four hours. Both tadalafil and vardenafil are labeled for precautious use with alpha-antagonists. However, tadalafil may be given concomitantly with tamsulosin 0.4 mg.

References:

1. Brown, Dana. The Management of Erectile Dysfunction and Identification of Barriers to Treatment. US Pharm. 2006;8:53-64.

2. Huang et al. Phosphodiesterase-5 (PDE5) Inhibitors In the Management of Erectile Dysfunction. Pharmacy and Therapeutics. 013 Jul; 38(7): 407, 414-419.

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4PMD: Blood Test Cooperative for Physicians

Patients seeking hormone and wellness related treatments sometimes encounter high costs associated with the required blood work. Being able to source affordable lab testing is key to having a program that employs laboratory assessment and early intervention to improve physiological, nutritional/hormonal, emotional/cognitive and physical function. Routine monitoring of patient biomarkers is scheduled throughout the year as an essential component for patients receiving hormone supplementation, interventional therapies, and/or fertility treatments. There are certain lab tests that need to be done annually to properly monitor men and women who are supplementing prescribed hormones. Some patients do not have third-party coverage for the laboratory biomarkers prescribed for these treatments; and the patient cost offered by the laboratory can be too expensive for the patient to afford, which therefore may result in non-compliance and low treatment retention.

Clinic Optimizers has partnered with a laboratory physician cooperative that contracts with national laboratories to receive wholesale prices for individual tests and test panels; the cost being significantly lower than what is typically billed by the laboratory directly to patients. The physician cooperative is called 4PMD (www.4PMD.com). 4PMD secured this low pricing by uniting physicians across the country who commonly prescribe wellness-related diagnostic tests within a self-pay practice model, so that they are able to order labs through the same account. This collaborative effort between 4PMD members results in the high volume purchasing authority needed to secure low wholesale ‘cash’ prices for catalog tests. This cost savings is then passed to the patient, who ends up paying an average 8% of the usual cost.

The affordable prices offered to patients through the clinic will help maintain the affordability of total treatment costs leading to high patient retention by mitigating the loss of patients who cannot otherwise afford annual treatment cost.

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