Somatropin [rDNA origin] for Injection - Genotropin Lyophilized Powder; human growth hormone, recombinant
Status - approved; marketed
Organizations involved:
Biovitrum AB – Manuf.; Tech.
Pharmacia Corp. – Former
Pfizer, Inc. – Intl. mark.; Parent
Pharmacia & Upjohn AB – R&D; Tech.; Former
Kabivitrum AB – R&D; Tech.; Former
Novo Nordisk Pharm., Inc. – Patent dispute
Jannsen Pharmaceutica N.V. – Patent dispute
Johnson & Johnson Co. – Parent
Cross ref.: See the Somatropin (hGH) Products entry (#247) and other somatropin product entries.
Description: Genotropin is a lyophilized (freeze-dried) formulation of recombinant somatropin (hGH) expressed in Escherichia coli (E. coli) bacteria. Its amino acid sequence and structure are identical to that of endogenous hGH and other E. coli expressed hGH products (other than somatrem/Protropin). The hGH is composed of 191 amino acids in a single chain cross-linked by two disulfide bridges with a molecular weight of 22,124 Dalton (22.124 kDa), and has a biological activity of 3 IU/mg of protein (using the current reference standard).
Genotropin is packaged in two-chamber cartridges and as Genotropin Miniquick, a single-use syringe device containing a two-chamber cartridge. Genotropin two-chamber cartridges have a front chamber containing either 1.5, 5.8, or 13.8 mg of somatropin and a rear chamber containing diluent for reconstitution and subcutaneous injection. The 1.5 mg front chamber contains 1.5 mg somatropin (~4.5 IU), glycine 27.6 mg, sodium dihydrogen phosphate anhydrous 0.3 mg, and disodium phosphate anhydrous 0.3 mg; with the rear chamber containing 1.13 mL Water for Injection. The 5.8 mg front chamber contains 5.8 mg somatropin (~17.4 IU), glycine 2.2 mg, mannitol 1.8 mg, sodium dihydrogen phosphate anhydrous 0.32 mg, and disodium phosphate anhydrous 0.31 mg; with the rear chamber holding 1.14 mL Water for Injection containing 0.3% m-cresol (as a preservative) and mannitol 45 mg. The 13.8 mg front chamber contains 13.8 mg somatropin (~41.4 IU), glycine 2.3 mg, mannitol 14.0 mg, sodium dihydrogen phosphate anhydrous 0.47 mg, and disodium phosphate anhydrous 0.46 mg; with the rear chamber holding 1.13 mL Water for Injection containing 0.3% m-cresol and mannitol 32 mg.
The Genotropin Miniquick single-use, two-chamber cartridge, syringe device provides doses of 0.2 mg to 2.0 mg in 0.2 mg increments. The front chamber contains somatropin, 0.22 to 2.2 mg (~0.66 to 6.6 IU), glycine 0.23 mg, mannitol 1.14 mg, sodium dihydrogen phosphate 0.05 mg, and disodium phosphate anhydrous 0.027 mg; with the rear chamber holding 0.275 mL Water for Injection containing mannitol 12.6 mg. Reconstituted Genotropin solution has an osmolality of ~300 mOsm/kg, and a pH of ~6.7. The concentration of the reconstituted solution varies by strength and presentation.
Nomenclature: Somatropin, rDNA/Pfizer [BIO]; Genotropin [TR]; Somatropin [rDNA origin] for Injection [FDA]; somatropin (human) [CAS]; 12629-01-5 [CAS RN]; human growth hormone, recombinant [SY]; hGH [SY]; somatomammotropin [SY]; Crescormon [TR foreign]; rhGH [SY]; NDC 0013-2649-02; NDC 0013-2654-02; NDC 0013-2650-02; NDC 0013-2655-02; NDC 0013-2651-02; NDC 0013-2656-02; NDC 0013-2652-02; NDC 0013-2657-02; NDC 0013-2653-02; NDC 0013-2658-02; NDC 0013-2626-94; NDC 0013-2626-81; NDC 0013-2616-94; NDC 0013-2616-81; NDC 0013-2646-94; NDC 0013-2646-81 [NDC]
Companies.: Genotropin was originally developed and manufactured by Kabi Pharmacia (Stockholm, Sweden), which subsequently merged into Pharmacia & Upjohn AB, a subsidiary part of Pharmacia Corp., which spun-off its Swedish biopharmaceutical business and facilities to Biovitrum AB, which later (2003) merged into Pfizer Corp. Genotropin continues to be manufactured by Biovitrum for Pharmacia/Pfizer.
Genotropin is marketed in the U.S. by Pharmacia Endocrine Care, a subsidiary of Pfizer, and internationally by Pharmacia/Pfizer and affiliates.
In Dec. 2006, Pfizer commissioned Skanska AB (www.skanska.com) to build a new plant in Strängnäs, Sweden, for manufacture of Genotropin, site of the product’s current manufacture.
Vetter Pharma-Fertigung manufactures the Genotropin MiniQuick single dose, disposable injection devices.
Manufacture: Somatropin is expressed in E. coli bacteria. Pharmacia reported, “The production process of Genotropin uses a copy of the natural hGH gene, not a hybrid minigene inserted into virus DNA as is used in other recombinant hGH preparations. The production method is based on normal bacterial cells (E. coli) which use natural controls for induction and synthesis. As a result, only minute amounts of periplastic E. coli proteins have been detected in preparations of Genotropin.”
hGH RNA was isolated from human cells, reverse transcriptase was used to obtain hGH cDNA, and the human signal sequence was replaced by an E. coli signal sequence (encoding for L-methionine). This gene for hGH with an amino acid N-terminal E. coli export signal peptide sequence was inserted into the bacterium using a circular plasmid vector. E. coli is then induced to express quantities of rhGH. The molecule is secreted into the periplastic space of the cell and is cleaved of its N-met signal sequence, resulting in the 191 amino acid sequence of native human hGH. Cell lysis and uncontrolled secretion of hGH into the culture medium are minimized during the production process, avoiding release of contaminants from E. coli cytoplasm. The outer cell walls of the bacterium are disrupted, such that the inner cell structure remains intact, avoiding contamination with E. coli polypeptides, and the recombinant protein is purified from the culture medium fluid. Periplastic E. coli proteins (PECP) are removed by the purification processes.
hGH is monitored during manufacture for structure, purity, and homogeneity of hGH protein. Tests used in quality control include: SDS-PAGE (sodium dodecylsulfate polyacrylamide gel electrophoresis); fingerprint (tryptic peptide mapping); size exclusion chromatography (SEC); ELISA immunoassays for E. coli periplastic protein; hydrophilic interaction HPLC (HI-HPLC); isoelectric focusing; rat weight gain bioassay of potency and specific activity; DNA hybridization (for E. coli DNA); N-terminal sequence analysis; sequence analysis for primary structure; C-terminal sequence analysis; amino acid analysis; high speed gel filtration (for dimers and polymers); ELISA for periplastic E. coli proteins (PECP); and rate nephelometry. A rat weight gain assay is used to assay biological potency. [Note, this manufacturing information is derived primarily from the “Production” sections of older (no longer available) U.S. and European Product Monographs from Pharmacia & Upjohn. manufacture is also discussed in Fryklund, L., “Production of Authentic Recombinant Somatropin,” Acta Pediatr Scand Suppl, 331, p. 5-8, 1987.
FDA class: Drug NDA
Approvals: Date =19950824; NDA (no. 020280); first approval; Indication = for the long-term treatment of children with growth hormone deficiency
Date =19971107; NDA supplement; Indication = for treatment of adults with growth hormone deficiency of either childhood or adult onset
Date = 20000621; NDA supplement, new indication with orphan designation; Indication = long-term treatment of growth failure in children with Prader-Willi syndrome (PWS)
Date = 20020703; NDA supplement; Indication = for long-term treatment of growth failure in children born small for gestational age who fail to manifest catch-up growth by two years of age.
Date = 20030328; NDA supplement; Indication = approval of alternative manufacturing site for dual-compartment injector cartridges
Date = 20030512; NDA supplement; Indication = "control supplement" approval
Date = 20070314; NDA supplement; Indication = harmonization of growth hormone product package inserts, particularly involving the CONTRAindications:,
WARNINGS, and PRECAUTIONS sectionsDate = 20070722; NDA supplement; Indication = "control supplement" approval
Date = 20070810; NDA supplement; Indication = "control supplement" approval
Date = 20080612; NDA supplement; Indication = approval for treatment of idiopathic short stature in pediatric patients whose epiphyses are not closed and for whom diagnostic evaluation excludes other causes associated with short stature that should be observed or treated by other means
Date = 20081014; NDA supplement; Indication = a change in the multi-dose product names Genotropin 5.8 mg (to 5 mg) and 13.8 mg (to 12 mg), and associated labeling revisions. Revised labeling includes the package insert, and the following for both the 5 mg and 12 mg products: two- chamber cartridge label, cartridge carton, Pen Device carton and Instructions for Use..
Date = 20081215; NDA supplement; Indication = approval of changes in the multi-dose product names Genotropin 5.8 mg (to 5 mg) and 13.8 mg (to 12 mg), and associated labeling revisions
Date = 20090115; NDA supplement; Indication = approval for the addition of a 31 gauge needle as an alternate needle for use with Genotropin Miniquick
Date = 20090512; NDA supplement; Indication = new manufacturer (Vetter Pharma-Fertigung, Ravensburg, Germany) for the Genotropin MiniQuick single dose, disposable injection devices available as 0.2 mg, 0.4 mg, 0.6 mg, 0.8 mg, 1.0 mg, 1.2 mg, 1.4 mg, 1.6 mg, 1.8 mg, and 2.0 mg.
Indications: [full text of "INDICATIONS AND USAGE” section from product insert/labeling; 10/2010]:
1.1 Pediatric Patients
GENOTROPIN (somatropin [rDNA origin] for injection) is indicated for the treatment of pediatric patients who have growth failure due to an inadequate secretion of endogenous growth hormone.
GENOTROPIN (somatropin [rDNA origin] for injection) is indicated for the treatment of pediatric patients who have growth failure due to Prader-Willi syndrome (PWS). The diagnosis of PWS should be confirmed by appropriate genetic testing (see CONTRAindications:).
GENOTROPIN (somatropin [rDNA origin] for injection) is indicated for the treatment of growth failure in children born small for gestational age (SGA) who fail to manifest catch-up growth by age 2 years.
GENOTROPIN (somatropin [rDNA origin] for injection) is indicated for the treatment of growth failure associated with Turner syndrome.
GENOTROPIN (somatropin [rDNA origin] for injection) is indicated for the treatment of idiopathic short stature (ISS), also called non-growth hormone-deficient short stature, defined by height standard deviation score (SDS) <-2.25, and associated with growth rates unlikely to permit attainment of adult height in the normal range, in pediatric patients whose epiphyses are not closed and for whom diagnostic evaluation excludes other causes associated with short stature that should be observed or treated by other means.
1.2 Adult Patients
GENOTROPIN (somatropin [rDNA origin] for injection) is indicated for replacement of endogenous growth hormone in adults with growth hormone deficiency who meet either of the following two criteria:
Adult Onset (AO): Patients who have growth hormone deficiency, either alone or associated with multiple hormone deficiencies (hypopituitarism), as a result of pituitary disease, hypothalamic disease, surgery, radiation therapy, or trauma; or
Childhood Onset (CO): Patients who were growth hormone deficient during childhood as a result of congenital, genetic, acquired, or idiopathic causes.
Patients who were treated with somatropin for growth hormone deficiency in childhood and whose epiphyses are closed should be reevaluated before continuation of somatropin therapy at the reduced dose level recommended for growth hormone deficient adults. According to current standards, confirmation of the diagnosis of adult growth hormone deficiency in both groups involves an appropriate growth hormone provocative test with two exceptions: (1) patients with multiple other pituitary hormone deficiencies due to organic disease; and (2) patients with congenital/genetic growth hormone deficiency.
Status: Genotropin was first launched in Sweden in 1987. Genotropin is now marketed worldwide. Outside of the U.S., Genotropin is mostly approved for chronic renal insufficiency and treatment of children with short stature associated with Turner Syndrome.
On July 30, 2003, FDA released revised warnings regarding use of Genotropin for Prader-Willi Syndrome (PWS) following postmarket reports of seven pediatric deaths associated with the product through April 1; and Pfizer revised the product insert/labeling.
In late April 2006, Novo Nordisk submitted an sNDA to FDA for approval of Genotropin for long-term treatment of patients with Turner Syndrome with open epiphyses.
In April 2007, Pfizer announced negotiation of two separate settlements with the U.S. Dept. of Justice (DOJ) concerning the off-label marketing of Genotropin and the inappropriate use of a vendor contract to increase the sales of other products by Pharmacia. These activities occurred at Pharmacia before it was acquired by Pfizer in 2003. Pfizer paid fines totaling $34.7 million.
In 15 Member States of the EU, Genotropin is authorized under a mutual recognition procedure on the basis of the initial authorization granted by Denmark on 7 May 1987. It has not received centralized EU approval.
Tech. transfer: Pfizer claims that U.S. patent protection for Genotropin expires in 2015.
The Orange Book reports 6,152,897 expiring on Nov 20, 2018; 5,716,338 expiring on Feb 10, 2015; and 5,435,076 and 5,501,673 expiring on Apr 16, 2013. This indicates patents expiring in late 2018.
Novo Nordisk holds a composition-of-matter patent, U.S. 5,633,352, covering aspects of recombinant human growth hormone expressed as a fusion protein with subsequent cleave of hGH (which does not appear to cover Genotropin’s method of manufacture as N-met-hGH with subsequent cleave of the terminal methionine).
On Oct. 6, 1997, Novo Nordisk filed a patent infringement lawsuit in the U.S. District Court alleging that other recombinant hGH manufacturers – Genentech, Inc., Eli Lilly & Co., Pharmacia & Upjohn Co., and Serono Labs. – each infringe its patent. This included Novo Nordisk citing Genotropin as infringing its patent. In Nov. 2000, Pharmacia Corp. announced an out-of-court settlement of the patent infringement suit. Terms were not disclosed, but Novo Nordisk reported that settlement would not significantly affect its financial status. In August 2004, in a separate case, the U.S. District Court of Delaware ruled that Novo Nordisk’s patent, 5,633,352, was invalid and unenforceable due to inequitable conduct. Savient Pharmaceuticals filed this suit in connection with its efforts to market its hGH, Tev-Tropin (see related entry), in the U.S. Novo Nordisk appealed this decision, and in 2004 cross-licensed its hGH patents with Savient (now Ferring)
U.S. 4,968,299, " Method and device for injection," assigned to KabiVitrum AB, now Biovitrum AB, covers aspects of the 2-chamber injection device. Patent protectino, including any extensions, expired June 28, 2008.
Disease: Genotropin is the only hGH product approved for Prader-Willi syndrome (PWS), a rare genetic disorder that causes short stature, an involuntary, continuous urge to eat, low muscle tone, and cognitive disabilities. It is estimated that 17,000 to 22,000 Americans have PWS. Although a rare disorder, PWS is one of the 10 most common conditions seen in genetics clinics and is the most common genetic cause of obesity (identified, to date).
Children with PWS are born with a dysfunction of the hypothalamus, the part of the brain that controls growth, pubertal development, and feelings of hunger and satiety (fullness). Despite having an insatiable appetite, people with PWS actually require much fewer calories to maintain an appropriate weight. Individuals with PWS have markedly decreased amount of muscle, very low muscle strength, and weak bones. These characteristics can lead to severe medical complications and lifestyle limitations. hGH treatment of children with PWS improves growth, increases muscle mass, and can help to reduce body fat, often resulting in a nearly normal body appearance and a greatly improved quality of life for the children and their families. Prior to Genotropin, there were few, if any, approved and effective treatment options for PWS.
Market: Total worldwide sales of Genotropin were $887 million in 2009; $898 million in 2008; $862 million in 2007; ~$795 million in 2006; ~$808 million in 2005; ~$712 million in 2004 (extrapolated from $535 million sales in the first three quarters); $481 million in 2003; $551 million in 2002; $511 million in 2001; and $460.8 million in 1999.
In 2009, Genotropin was reported to have the leading market share, at 28%, in the worldwide hGH market (then about $2.75-$3.0 billion).
Genotropin is the worldwide leader in hGH sales in terms of market share (but not in the U.S.). About one-third of sales are in the U.S. The worldwide sales decrease in 2006 was attributed to increased competition, including from biogenerics, e.g., Valtropin.
The 2007 Average Wholesale Price (AWP) for Genotropin is $291.69/5.8 mg prefilled syringes, with a Direct Price (DP; discount price) of $243.07, $1,458.42 for five, with a DP of $1,215.35; and $700.34/12.8 mg vial, with a DP of $583.37, and $3,500.22 for five, with a DP of $2,916.85 (Red Book, 2007). The 2007 AWP for Genotropin MiniQuick is $81.67 for seven 0.2 mg prefilled syringes, with a DP of $68.06; $163.34 for seven 0.4 mg syringes, with a DP of $136.12; $245.02 for seven 0.6 mg syringes, with a DP of $204.18; $326.69 for seven 0.8 mg syringes, with a DP of $272.24; $408.36 for seven 1.0 mg syringes, with a DP of $240.30; $490.03 for seven 1.2 mg syringes, with a DP of $408.36; $571.70 for seven 1.4 mg syringes, with a DP of $478.42; $653.38 for seven 1.6 mg syringes, with a DP of $544.48; $735.05 for seven 1.8 mg syringes, with a DP of $612.54; and $816.72 for seven 2.0 mg syringes, with a DP of $680.60 (Red Book, 2007).
In Dec. 2009, the National Institute for Health and Clinical Excellence, U.K., recommended the use of Genotropin to treat children with short stature due to: growth hormone deficiency; Turner syndrome; Prader–Willi syndrome; chronic renal insufficiency; being born small for gestational age; and short stature homeobox-containing gene (SHOX) deficiency, i.e., NICE ruled that uled that Genotropin is indeed a cost-effective use of National Health Service (NHS) resources. The cost of treatment in the U.K. varies depending on the child’s weight or body surface area and the different therapies used. Genotropin (and Saizen) are the most expensive somatropins in the U.K. at £23.18 per mg and Humatrope the cheapest at £18.00 per mg. NICE also noted that therapy with Genotropin should be discontinued: if there growth velocity is less than 50% from baseline in the first year of treatment; final height is approached and growth velocity is less than 2cm total growth in one year; there are “insurmountable problems” with adherence; or final height is attained.
Companies involvement:
Full monograph
254 Somatropin, rDNA/Pfizer
Nomenclature:
Somatropin, rDNA/Pfizer [BIO]
Genotropin [TR]
Somatropin [rDNA origin] for Injection [FDA]
somatropin (human) [CAS]
12629-01-5 [CAS RN]
hGH [SY]
human growth hormone, recombinant [SY]
rhGH [SY]
somatomammotropin [SY]
Crescormon [TR foreign]
NDC 0013-2649-02; NDC 0013-2654-02; NDC 0013-2650-02; NDC 0013-2655-02; NDC 0013-2651-02; NDC 0013-2656-02; NDC 0013-2652-02; NDC 0013-2657-02; NDC 0013-2653-02; NDC 0013-2658-02; NDC 0013-2626-94; NDC 0013-2626-81; NDC 0013-2616-94; NDC 0013-2616-81; NDC 0013-2646-94; NDC 0013-2646-81 [NDC]
molecular weight (kDa) = 22
FDA Class: Drug NDA
Year of approval (FDA) = 1997
Date of 1st FDA approval = 19971107
(in format YYYYMMDD)
Biosimilars/biobetters-related U.S. Patents: | expired, with generic drug versions, e.g., Omnitrope, already marketed; 2006 (year of Omnitrope approval) arbitrarily used as expiration date |
U.S. Patent Expiration Year: | 2011 |
U.S. Biosimilars Data Exclusivity Expiration: | 2009 |
U.S. Biosimilars Orphan Exclusivity Expiration: | 2004 |
U.S. Biosimilars Launchability Year: | 2009 |
U.S. Biobetters Launchability Year: | 2006 |
Biosimilars/biobetters-related EU Patents: | expired; biosimilars, e.g., Omnitrope, already marketed in EU; 2006 (year of Omnitrope approval) arbitrarily used as expiration date |
EU Patent Expiration Year: | 2006 |
EU Biosimilars Data Exclusivity Expiration: | 1997 |
EU Biosimilars Orphan Exclusivity Expiration: | 1887 |
EU Biosimilars Launchability Year: | 2006 |
EU Biobetters Launchability Year: | 2006 |
Index Terms:
biopharmaceutical products
exempt from CBER lot release requirements
growth hormones
hormones
recombinant DNA
bacterial culture <!-- bacterialculture -->
Escherichia coli (E. coli)
cresol, meta-
disodium phosphate
glycine
lyophilized (freeze-dried)
mannitol
periplastic E. coli proteins (PECP)
sodium dihydrogen phosphate
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
orphan status
EU200 Currently Approved in EU
UM001 Marketed Product in US
US200 Currently Approved in US
EM001 Marketed Product in EU
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