(Note: This import alert represents the Agency's current guidance to FDA field personnel regarding the manufacturer(s) and/or products(s) at issue. It does not create or confer any rights for or on any person, and does not operate to bind FDA or the public).
Import Alert # 66-71
Published Date: 03/18/2011
Import Alert Name:
"Detention Without Physical Examination of Human Growth Hormone (HGH), Also Known As Somatropin"
Reason for Alert:
Human Growth Hormone (HGH) is the active ingredient in a number of human prescription drugs approved for marketing in the U.S. under new drug applications (NDAs). FDA-approved HGH can be legally prescribed for a limited number of conditions including:
* hormonal deficiency that causes short stature in children;
* long-term treatment of growth failure due to lack of exogenous GH secretion;
* long-term treatment of short stature associated with Turner syndrome;
* adult short bowel syndrome;
* adult deficiency due to rare pituitary tumors or their treatment; and
* muscle-wasting disease associated with HIV/AIDS.
HGH has important benefits, but also serious, known risks. Among the possible long-term side effects of HGH is an increased risk of cancer, and other dangerous side effects have been reported, including nerve pain and elevated cholesterol and glucose levels. For this reason, HGH is carefully regulated in the U.S.
The cost of approved HGH products is high, averaging several hundred dollars per dose. Because of this high cost, HGH drugs have been counterfeited and unapproved HGH products are offered for sale to U.S. consumers. For example, we have encountered HGH products imported as a lyophilized powder and declared as an active pharmaceutical ingredient (API) for pharmacy compounding. Some pharmacies promote compounded HGH for anti-aging purposes. It is sold as a "fountain of youth" in longevity clinics and to build body mass, weight loss, increase libido, and gain stamina. None of these indications are in the labeling of the FDA approved products.
The agency is aware of unapproved HGH finished dosage form products being imported into the U.S. and recently noted a large increase of HGH being offered for import for pharmacy compounding. If the drug is bought from foreign sources or over the Internet, safeguards built into the U.S. drug distribution system may be bypassed, placing consumers who use HGH at higher risk.
Section 303(e)(1) of the FDCA, 21 U.S.C. 333(e) (1), prohibits knowingly distributing, or possessing with the intent to distribute, HGH for any use in humans other than the treatment of a disease or other recognized medical condition, where such use has been authorized by the Secretary of Health and Human Services (HHS) under section 505 of the FDCA (21 U.S.C. 355) and pursuant to the order of a physician. The Secretary of HHS has not authorized, for example, any HGH use for anti-aging, bodybuilding, or athletic enhancement. Thus, distributing, or possessing with the intent to distribute, HGH for these uses or any other unapproved use violates section 303(e)(1) of the FDCA. A violation of section 303(e)(1) carries up to 5 years imprisonment and fines and, if the offense involves an individual under the age of 18 years of age, up to 10 years imprisonment and fines.
HGH products are new drugs and cannot be legally marketed in the U.S. without an approved application. The few HGH products that have been approved for sale by FDA are sold either in liquid form or as lyophilized powders that are labeled for constitution by the health care professionals who dispense them. Accordingly, FDA considers both imported HGH lyophilized powder products and liquid HGH products to be finished dosage form drugs, not APIs. Unless these products are the subject of approved new drug applications, they violate section 505 of the FDCA, 21 U.S.C. 355, and may not be legally imported into the U.S. Some HGH marketers may claim that their HGH drug products are intended for use in pharmaceutical compounding. These drugs should be evaluated on a case-by-case basis considering the factors in FDA Compliance Policy Guide, section 460.200, and the specific prohibitions set forth in section 303(e) of the FDCA, 21 U.S.C. 333(e). The use of HGH in pharmacy compounding is addressed in more detail, below.
Some HGH marketers may claim that their HGH products are dietary supplements. FDA first approved HGH as a new drug in 1940, and HGH was not marketed as a dietary supplement, or as a food, before then. Accordingly, HGH is excluded from the definition of a dietary supplement under section 201(ff) (1) of the FDCA (21 U.S.C. 321(ff)(3)(A)) because growth hormone was an article approved as a new drug under section 505 of the FDCA (21 U.S.C. 355) before its introduction as a dietary supplement.
Districts may detain without physical examination all shipments of HGH finished drug products and all shipments of HGH APIs intended for the manufacture of a drug that is not subject to an approved new drug application (NDA). If field personnel are unsure of whether the HGH product at issue is an API or finished drug product, those personnel should contact CDER Compliance at the number listed below for further guidance.
(1) Finished drug products that are covered by approved NDAs;
Note: Shipments should be intended for persons who can lawfully possess and/or distribute HGH;
(2) APIs that are intended for use in the manufacture of finished drug products subject to approved or pending applications and where the approved/pending application covers the production and delivery of the API to the application holder by persons named in the application;
Note: Districts should contact the CDER Import-Export Team if they cannot confirm in CDER's databases that an HGH finished drug product is covered by an approved application or if an API is covered by an approved or pending application.
(3) APIs that are intended solely for tests in vitro or in animals used only for laboratory research, and are labeled in accordance with 21 CFR 312.160(a)(1)(i);
(4) APIs that will be used for non-clinical research and development, under the conditions set forth in 21 CFR 201.125;
Note: Importers of HGH API that claim to fall within exceptions (3) or (4) may obtain release of the detained substance only by providing documentation establishing that the substance meets the conditions set forth in 21 CFR 312.160 or 201.125.
(5) HGH intended for pharmacy compounding should be reviewed on a case-by-case basis. Consistent with its Compliance Policy Guide on human drug compounding and the prohibitions set forth in section 303(e) of the Act, 21 U.S.C. 333(e), FDA may exercise its enforcement discretion in certain instances to allow the importation of HGH for use in traditional pharmacy compounding.
In general, FDA should exercise its enforcement discretion only in those instances where (1) the compounded product is intended for a use that has been authorized by FDA for HGH under section 505 of the FDCA; and (2) the drug will be compounded to meet the individual medical needs of a specific patient who cannot be treated with an FDA-approved HGH drug product (e.g., the patient is allergic to the commercially available FDA-approved HGH product.
To this end, FDA should consider the following factors when making a determination about whether it is appropriate to exercise enforcement discretion to allow entry of a shipment:
* the indication for which the HGH is being compounded;
* information indicating the individual medical need for a specific patient; e.g., letter from physician or prescription;
* the volume of HGH imported and the appropriateness of the volume, based on considerations such as the amount of HGH used to compound a typical prescription;
* the medical need for the compounded product;
* the identity of the firms that will receive HGH from the shipment;
* the identity of the firms that have received the HGH in the past;
* the presence of statements on the HGH label, at the time that it is imported or offered for import, that the HGH is "For Prescription Compounding" and "Rx only";
* whether the HGH meets official compendia requirements where applicable (for example, as shown on a certificate of analysis), and
* whether the HGH comes from a firm that complies with drug registration and listing requirements
Additionally, the importer should affirm in writing that the HGH will be used solely for human drug compounding.
In order to facilitate FDA's case-by-case review, the information identified in points (1)-(5) above should be made available to FDA at the time the offer to import is made.
Discretionary release of these products under the Personal Importation guidance of Chapter 9 of the Regulatory Procedures Manual (RPM) is not appropriate.
If the District Offices have questions concerning the importation of Human Growth Hormone (HGH) they should contact CDER/OC/DNLC immediately.
Human Growth Hormone (HGH); Somatropin
For finished drug products:
"The article is subject to refusal of admission pursuant to Section 801(a)(3) in that it appears to be a new drug within the meaning of Section 201(p) without an effective new drug application (NDA)[Unapproved New Drug, Section 505(a)".] "The article is subject to refusal of admission pursuant to section 801(a)(3) in that it appears to be misbranded in that it lacks adequate directions for its intended use. [Misbranding, Section 502(f)(1)]."
OASIS charge code - DIRECTIONS
For all active pharmaceutical ingredients (APIs), including those APIs intended for use in pharmaceutical compounding:
"The article is subject to refusal of admission pursuant to section 801(a)(3) of the FDCA because it appears to be misbranded in that it lacks adequate directions for its intended use and it is not exempt from this requirement. (Misbranding, section 502(f)(1) of the FDCA)"
Human growth hormone (hGH) is a naturally occurring polypeptide hormone secreted by the pituitary gland and is essential for body growth. Daily secretion of hGH increases throughout childhood, peaking during adolescence, and steadily declining thereafter. In 1985, synthetic hGH was developed and approved by the FDA for specific uses. However, it is commonly abused by athletes, bodybuilders, and aging adults for its ability increase muscle mass and decrease body fat, as well as its purported potential to improve athletic performance and reverse the effects of aging.
Several FDA-approved injectable hGH preparations are available by prescription from a supervising physician for clearly and narrowly defined indications. In children, hGH is approved for the treatment of poor growth due to Turner’s syndrome, Prader-Willi syndrome, and chronic renal insufficiency, hGH insufficiency/deficiency, for children born small for gestational age, and for idiopathic short stature. Accepted medical uses in adults include the treatment of the wasting syndrome of AIDS and hGH deficiency. The recommended dosage is 40 g/kg/day for children and 25 g/kg/day for adults. The FDA-approved injectable formulations are available as liquid preparations, or as powder with a diluent for reconstitution.
Chemistry and Pharmacology:
Using recombinant DNA technology, two forms of synthetic hGH were developed, somatropin and somatrem. Somatropin is identical to the endogenous pituitary-derived hGH, whereas somatrem has an extra amino acid on the N-terminus. Both synthetic forms have similar biological actions and potencies as the endogenous hGH polypeptide. Synthetic hGH also is chemically indistinguishable from the naturally occurring hormone in blood and urine tests.
hGH binds to growth hormone receptors present on cells throughout the body. hGH functions to regulate body composition, fluid homeostasis, glucose and lipid metabolism, skeletal muscle and bone growth, and possibly cardiac functioning. Sleep, exercise, and stress all increase the secretion of hGH.
The use of hGH is associated with several adverse effects including edema, carpal tunnel syndrome, joint pain, muscle pain, and abnormal skin sensations (e.g., numbness and tingling). It may also increase the growth of pre-existing malignant cells, and increase the possibility of developing diabetes.
hGH is administered by subcutaneous or intramuscular injection. The circulating half-life of hGH is relatively short half-life (20-30 minutes), while its biological half-life is much longer (9-17 hours) due to its indirect effects.
Human growth hormone is illicitly used as an anti-aging agent, to improve athletic performance, and for bodybuilding purposes. It is marketed, distributed, and illegally prescribed off-label to aging adults to replenish declining hGH levels and reverse age-related bodily deterioration. It is also abused for its ability to alter body composition by reducing body fat and increasing skeletal muscle mass. It is often used in combination with other performance enhancing drugs, such as anabolic steroids. Athletes also use it to improve their athletic performance, although the ability of hGH to increase athletic performance is debatable.
Athletes, bodybuilders, and aging adults are the primary abusers of hGH. Because the illicit use of synthetic hGH is difficult to detect, its use in sports is believed to be widespread. Over the past few years, numerous professional athletes have admitted to using hGH. Bodybuilders, as well as celebrities also purportedly use it for its ability to alter body composition. Aging adults looking to reverse the effects of aging are increasingly using synthetic hGH.
The illicit distribution of hGH occurs as the result of physicians illegally prescribing it for off-label uses, and for the treatment of FDA-approved medical conditions without examination and supervision. Illicit distribution also involves diverted hGH obtained through theft, smuggled hGH illegally imported from other countries, and counterfeit hGH.
The illicit distribution of injectable synthetic hGH formulations is thought to be primarily through Internet pharmacies, as well as wellness and anti-aging clinics and websites. Internet pharmacies are often partnered with a physician willing to write prescriptions for a fee without a physical examination. Individuals may also obtain hGH without a prescription through the black market. hGH is often marketed with other performance enhancing drugs (e.g., anabolic steroids).
According to the National Forensic Laboratory Information System (NFLIS), law enforcement officials submitted 30 hGH items/exhibits to state and local forensic laboratories between 2005 and 2010. Various oral preparations (e.g., sprays and pills) purported to contain hGH are also marketed and distributed. However, hGH is only available in the injectable form. The hGH molecule is too large for absorption across the lining of the oral mucosa and the hormone is digested by the stomach before absorption can occur.
Human growth hormone is not controlled under the Controlled Substances Act (CSA). However, as part of the 1990 Anabolic Steroids Control Act, the distribution and possession, with the intent to distribute, of hGH "for any use…other than the treatment of a disease or other recognized medical condition, where such use has been authorized by the Secretary of Health and Human Services…and pursuant to the order of a physician…" was criminalized as a five-year felony under the penalties chapter of the Food, Drug, and Cosmetics Act of the FDA.
hGH is listed by the World Anti-Doping Agency and the International Olympic Committee as a performance enhancing drug barring athletes from using it.
Comments and additional information are welcomed by the Office of Diversion Control, Drug and Chemical Evaluation Section.
Fax 202-307-1263, telephone 202-307-7183, or Email ODE@usdoj.gov.
Drug Enforcement Administration
Office of Diversion Control Drug & Chemical Evaluation Section ANABOLIC STEROIDS
Anabolic steroids are a class of drugs with a basic steroid ring structure that produce anabolic effects and androgenic effects. Athletes, bodybuilders, and others abuse anabolic steroids with the intent to improve athletic performance, muscle strength, and appearance.
Chemistry and Pharmacology:
Most anabolic steroids are synthetically manufactured variations of testosterone. No anabolic steroid is devoid of androgenic effects. Activation of androgen receptors in various cells and tissues primarily mediate the anabolic and androgenic effects. The anabolic effects include the growth of skeletal and cardiac muscle, bone, and red blood cells, whereas the androgenic effects include the development of male secondary sexual characteristics.
The adverse effects associated with anabolic steroids are dependent on the age of the user, the sex of the user, the anabolic steroid used, the amount used, and the duration of use. In adolescents, use can permanently stunt growth. In women, use can induce permanent physical changes including deepening of the voice, increased facial and body hair growth, and the lengthening of the clitoris. In men, use can cause shrinkage of the testicles, enlargement of the male breast tissue, and sterility. Anabolic steroid use can damage the liver and can cause an increase in cholesterol levels. Anabolic steroid use can also induce psychological effects such as aggression, increased feelings of hostility, psychological dependence, and addiction. Upon abrupt termination of long term anabolic steroid use, abusers may experience withdrawal symptoms including severe depression.
Anabolic steroids are abused with the intent to enhance athletic performance, increase muscle strength, and improve appearance. The doses used are often 10 to 100 times higher than the doses used to treat medical conditions. Users typically take two or more anabolic steroids at the same time in a cyclic manner believing that this will improve their effectiveness and minimize the adverse effects. Anabolic steroid abuse is often accompanied by the use of other drugs.
Anabolic steroids are abused by professional, amateur, recreational athletes, and bodybuilders. Adolescents and young adults in the general population also abuse steroids for its muscle growth effects.
In the 2010 Monitoring the Future (MTF) study, which surveys eighth, tenth, and twelfth grade students, 1.1%, of eighth graders, 1.6% of tenth graders, and 2.0% of twelfth graders reported using steroids at least once in their lifetimes. Regarding the ease by which steroids can be obtained, 14.2% of eighth graders, 20.3% of tenth graders, and 27.3% of twelfth graders reported that steroids were "fairly easy" or "very easy" to obtain.
Anabolic steroids are available as injectable preparations, tablets and capsules, and gels and creams. Most anabolic steroids sold illegally in the U.S. come from abroad. The Internet is the most widely used means of buying and selling anabolic steroids. However, there is also evidence of diversion through unscrupulous pharmacists, doctors, and veterinarians.
New steroids, which have not undergone safety or efficacy testing in the U.S., have appeared over the years. Some of these "designer steroids" were supplied to athletes to avoid drug testing detection. Commercially available dietary supplements are sold purporting to contain novel anabolic steroids. These products, which are advertised to build muscle and increase strength, are readily available on the Internet.
The National Forensic Laboratory Information System (NFLIS) and System to Retrieve Information from Drug Evidence (STRIDE) indicate that testosterone, methandrostenolone, stanozolol and nandrolone and are the four most frequently encountered steroids by the federal, state, and local forensic laboratories in 2010 and in the first quarter of 2011. There were 1,643 exhibits identified as testosterone, 356 exhibits identified as methandrostenolone, 347 identified as stanozolol and 346 identified as nandrolone in 2010. In the first quarter of 2011, there were 347 exhibits, 62 exhibits, 63 exhibits and 66 exhibits identified as testosterone, methandrostenolone, stanozolol and nandrolone, respectively.
By enacting the Anabolic Steroid Control Acts of 1990 and 2004, Congress placed a total of 59 anabolic steroids in schedule III of the Controlled Substances Act. The salts, esters, and ethers of these 59 anabolic steroids are also controlled. Congress provided a definition to administratively classify additional steroids as schedule III anabolic steroids.
In the U.S., only a small number of anabolic steroids are approved for either human or animal use. Testosterone and several of its esters, as well as methyltestosterone, nandrolone decanoate, and oxandrolone are the main anabolic steroids currently prescribed in the U.S. Some of the approved medical uses include the treatment of testosterone deficiency, delayed puberty, anemia, breast cancer, and tissue wasting resulting from AIDS. Trenbolone, boldenone and mibolerone are used only in veterinary medicine.
Comments and additional information are welcomed by the Office of Diversion Control, Drug and Chemical Evaluation Section.
Fax 202-353-1263, Telephone 202-307-7183, or Email ODE@usdoj.gov
December 23, 2010 — The US Food and Drug Administration (FDA) is looking into results from a French study that found that persons with idiopathic growth hormone deficiency and idiopathic or gestational short stature who were treated with long-term recombinant human growth hormone during childhood were at a small increased risk for death compared with individuals in the general French population.
The FDA made the announcement Thursday via its MedWatch Safety Information and Adverse Event Reporting Program. The agency did not define "small" or state anything more specific on the risks seen in the Santé Adulte GH Enfant (SAGhE) study.
"FDA is currently reviewing all available information on this potential risk and will communicate any new recommendations once it has completed its review," the posting states.
"At this time, FDA recommends that patients continue their recombinant human growth hormone treatment as prescribed by their healthcare provider."
Recombinant human growth hormone, also known as somatropin (rDNA origin) injection, is marketed under the following brand names in the United States: Genotropin (Pfizer), Humatrope (Lilly), Norditropin (Novo Nordisk), Nutropin and Nutropin AQ (Genentech), Omnitrope (Sandoz), Saizen (EMD Serono), and Tev-Tropin (Teva Pharmaceuticals).
Recombinant human growth hormone stimulates tissue growth, linear growth, and protein, carbohydrate, lipid, and mineral metabolism. It is approved for various indications in adults and children.
In the United States, recombinant human growth hormone is used in children to treat short stature resulting from growth hormone deficiency (including idiopathic growth hormone deficiency, Turner syndrome, Noonan syndrome, Prader-Willi syndrome, short stature homeobox-containing gene deficiency, chronic renal insufficiency, idiopathic short stature, and children small for gestational age).
The French SAGhE Study
The French SAGhE study, part of the larger SAGhE Study in Europe, was started in 2007 in collaboration with Agence Française de Sécurité Sanitaire et des Produits de Santé, French Drug Agency, the Ministry of Health, and the National Cancer Institute of France. The aims of the study are to evaluate the long-term health of patients who have been treated with biosynthetic growth hormone in childhood, including long-term mortality and long-term cancer incidence. The SAGhE study in France has included 10,489 patients.
In SAGhE, there was a 30% increased risk for death with recombinant human growth hormone therapy compared with the general French population. There were 93 deaths in the treated group compared with 70 expected deaths.
The increase in mortality risk could be related to bone cancers and to cardiovascular diseases and cerebrovascular events — primarily subarachnoid and intracerebral hemorrhage.
The risk for death appeared to be dose-related and usually occurred in individuals given doses higher than typically prescribed for pediatric growth hormone deficiency.
The approved doses in the United States for pediatric growth hormone deficiency are less than 50 μg/kg/day, except during puberty, when a higher dose regimen is approved for a limited duration. The currently approved maximum dose for short stature indications other than growth hormone deficiency is 69 μg/kg/day, or 0.48 mg/kg/week.
More information on the French SAGhE study and the SAGhE Study in Europe can be found on the study's Web site.
Adverse events related to recombinant human growth hormone products should be reported to the FDA's MedWatch reporting program by telephone at 1-800-FDA-1088, by fax at 1-800-FDA-0178, online at http://www.fda.gov/medwatch, or by mail to 5600 Fishers Lane, Rockville, Maryland 20852-9787.
The FDA is notifying the public about new safety information concerning products marketed for body building and increasing muscle mass. The FDA has sent a Warning Letter to a manufacturer of body building supplements that claim to contain steroid-like ingredients, but in fact contain synthetic steroids. The products named in the Warning Letter are marketed by American Cellular Laboratories, Inc., and include “TREN-Xtreme,” “MASS Xtreme,” “ESTRO Xtreme,” “AH-89-Xtreme,” “HMG Xtreme,” “MMA-3 Xtreme,” “VNS-9 Xtreme,” and “TT-40-Xtreme.”
The FDA has received reports of serious adverse events associated with the use of these products and other similar products. Products like these are frequently marketed as alternatives to anabolic steroids for increasing muscle mass and strength and are sold both online and in retail stores. They are often promoted to athletes to improve sports performance and to aid in recovery from training and sporting events. Although products containing synthetic steroids are frequently marketed as dietary supplements, they are NOT dietary supplements, but instead are unapproved new drugs that have not been reviewed by the FDA for safety and effectiveness.
Adverse event reports received by the FDA for body building products that are labeled to contain steroids or steroid alternatives involve men (ages 22-55) and include cases of serious liver injury, stroke, kidney failure and pulmonary embolism (blockage of an artery in the lung).
Due to the potentially serious health risks associated with using these types of products, the FDA recommends that consumers immediately stop using all body building products that claim to contain steroids or steroid-like substances. Consumers should consult their health care professional if they are experiencing symptoms possibly associated with these products, particularly nausea, weakness or fatigue, fever, abdominal pain, chest pain, shortness of breath, jaundice (yellowing of the skin or whites of the eyes) or brown/discolored urine. The FDA also recommends that consumers talk with their health care professional about any body building supplements they are taking or planning to take, particularly if they are uncertain about a product’s ingredients.
Health care professionals are advised to ask their patients about any over-the-counter products they may be using, including products marketed as dietary supplements. Additionally, health care professionals should be alert to patients presenting with the warning signs that may be associated with the use of steroids or steroid-like substances, including liver injury, kidney failure, stroke, and hormone-associated adverse effects, such as blood clots, including pulmonary embolism and deep vein thrombosis.
Health care professionals and consumers are encouraged to report any adverse events related to the use of these products to FDA's MedWatch Adverse Event Reporting program, either online, by regular mail or by fax, using the contact information at the bottom of this page.
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