Status - still FDA approved, but discontinued/withdrawn in 2004

Organizations involved:

Genentech, Inc. – Manuf.; R&D; Tech.; USA mark.

Alkermes, Inc. – Manuf.; R&D; Tech.

Schwartz Pharma AG – Europe mark.

Dainippon Sumitomo Pharm. Co., Ltd. – Japan mark.

Novo Nordisk A/S – Patent Dispute

City of Hope National Medical Center – Tech.; Patent dispute

Cross ref.: See the Somatropin Products entry above and the other somatropin product entries below, including the entries for Nutropin (non-encapsulated) and Protropin, both also from Genentech.

Description: Somatropin (rDNA origin) for suspension or Nutropin Depot is a solid powder, microsphere encapsulated, long-acting formulation of lyophilized (freeze-dried) recombinant Escherichia coli (E. coli) expressed somatropin (human growth hormone; hGH). Nutropin Depot contains the same recombinant hGH as in Nutropin and Nutropin AQ, and is similarly identical in many respects, e.g., primary amino acid sequence and activity, to pituitary-derived hGH. See the Nutropin/Nutropin AQ entry above for further information about this recombinant hGH.

The Nutropin Depot formulation consists of micronized particles of lyophilized rhGH embedded in biocompatible, biodegradable polylactide-coglycolide (PLG) polymer microspheres (using ProLease technology licensed from Alkermes). The ProLease formulation process is designed to assure the stability of fragile proteins and other agents during manufacturing, storage, and after injection and release in the body. This controlled (slow) release formulation requires only one or two doses per month, unlike other hGH products which are not formulated for controlled release and generally require multiple doses per week or even daily.

Nutropin Depot is packaged as a kit with a single-use 3 mL vial containing either 13.5 mg, 18 mg, or 22.5 mg of sterile, preservative-free, microencapsulated, somatropin powder per vial, along with diluent for suspension for subcutaneous injection. Prior to administration, the powder is suspended in Diluent for Nutropin Depot (a sterile aqueous solution). Nutropin Depot powder may only be suspended in the Diluent for Nutropin Depot supplied in the kit and administered with the supplied needles. Each 13.5 mg 3 mL single-use vial of Nutropin Depot contains 13.5 mg somatropin, 1.2 mg zinc acetate, 0.8 mg zinc carbonate, and 68.9 mg polylactide-coglycolide (PLG). Each 18 mg 3 mL single-use vial of Nutropin Depot contains 18 mg somatropin, 1.6 mg zinc acetate, 1.1 mg zinc carbonate, and 91.8 mg PLG. Each 22.5 mg 3 mL single-use vial of Nutropin Depot contains 22.5 mg somatropin, 2.0 mg zinc acetate, 1.4 mg zinc carbonate, and 114.8 mg PLG. Each dosage size contains an average of rhGH microspheres to ensure delivery of the labeled contents. Each 1.5 mL single-use vial of Diluent for Nutropin Depot contains 30 mg/mL carboxymethylcellulose sodium salt, 1 mg/mL polysorbate 20 (Tween 20), 9 mg/mL sodium chloride, and Sterile Water for Injection; at pH 5.8-7.2. Nutropin Depot is stored at 2°C–8°C(36°F–46°F; refrigerated). The expiration date is on the product label.

Nutropin Depot (and Nutropin AQ) may contain up to 15% deaminated somatropin at expiration. This has been extensively studied and shown safe and fully active.

Nomenclature: Somatropin, rDNA, depot [BIO]; Nutropin Depot [TR]; Somatropin (rDNA origin) for Injectable Suspension [FDA]; hGH [SY]; human growth hormone, recombinant [SY]; rhGH [SY[; NDC 50242-032-3; NDC 50242-034-41; NDC 50242-036-54 [NDC]

Companies.: Nutropin, the active ingredient, recombinant E. coli-expressed somatropin (rhGH), was developed and is manufactured by Genentech, Inc. Alkermes manufactures the ProLease formulation (performs encapsulation) at its facilities.

Nutropin Depot is marketed in the U.S. by Genentech. [Note, discontinuation of product wasannounced June, 1, 2004]. It is marketed in Canada by Genentech Canada (joint venture of Genentech and Boehringer Ingelheim GmbH). Sumitomo, now Dainippon Sumitomo Pharma Co., Ltd., has exclusive Japanese rights, and Schwartz Pharma AG has European marketing rights.

Manufacture: The use of a stabilized solid under low temperatures is the key to Alkermes’ ProLease microencapsulation process. First, recombinant somatropin is formulated with stabilizing agents and lyophilized as a fine powder. The powder is then microencapsulated or coated with polylactide-coglycolide (PLG) polymer at very low temperatures.

FDA class: Drug NDA

Approvals: Date = 19991223; first approval, NDA 21-075; orphan drug designation (expires 12/23/2006)

Date = 20020423; NDA supplement; Indication = for use with the Nutropin AQ Pen injection system

Indications: [full text of indications: and Usage from product insert/labeling at time of approval]:

Nutropin Depot [somatropin (rDNA origin) for injectable suspension] is indicated for the long-term treatment of growth failure due to a lack of adequate endogenous GH secretion.

Considerations for use—As with any GH treatment, patients should be monitored closely throughout therapy for growth response to Nutropin Depot. Failure to respond adequately requires careful assessment, as described under DOSAGE AND ADMINISTRATION. Patients for whom no discernible cause is found should be considered for a course of treatment with a daily form of rhGH. Experience in patients who were treated with daily GH and switched to Nutropin Depot is limited.

Status: The NDA was filed on June 25, 1999, and approved on Dec. 23, 1999; review time = .5 year. Approval recognized that Genentech had, “fulfilled the pediatric study requirement at this time” and the company acknowledged commitments to complete Phase IV studies. The product was launched by Genentech in the U.S. on June 28, 2000.

On June 1, 2004, Genentech and Alkermes announced the discontinuation of manufacture and marketing of Nutropin Depot, “based on the significant resources required by both companies to continue manufacturing and commercializing the product.” Stocks ran out and sales halted in 2004.

Tech. transfer: See the Nutropin entry for further information about relevant Genentech’s hGH patents and patent disputes.

The Orange Book cites 5,763,394, "Human growth hormone aqueous formulation," expiring June 9, 2015.

EP patents apparently related to 5,763,394 include EP0652766, "HUMAN GROWTH HORMONE AQUEOUS FORMULATION," expiring in 2013; and EP040987 and EP0603159, "Human growth hormone formulation," expiring in 2009.

Trials: In late 2003, a study of Nutropin Depot in patients with adult growth hormone deficiency was reported to have met its primary endpoint, and Genentech and Alkermes were reportedly considering a potential filing of these data with the FDA.

Medical: For once-monthly administration, it is recommended that a subcutaneous (SC) injection at a dosage of 1.5 mg/kg body weight be administered on the same day of each month. Patients over 15 kg require more than one injection per dose. For twice-monthly administration, it is recommended that a SC injection at a dosage of 0.75 mg/kg body weight be administered twice each month on the same days of each month. Patients over 30 kg require more than one injection per dose.

Cross ref.: See the Nutropin entry above for sales information.

With the discontinuation of Nutropin Depot, Genentech moved current users to its other hGH products (Nutropin).

The 2005 Average Wholesale Price (AWP) was $679.82/ 13.5 mg vial; $906.42/18 mg vial; and $1,133.03/22.5 mg vial (Red Book, 2005). Note, these AWPs are unchanged from 2004, and the product was no longer being manufactured and marketed in 2005 (although remaining stock still might still have been available for purchase).

Ongoing: In Jan. 1995, Genentech and Alkermes signed a patent licensing and collaborative R&D agreement to develop sustained release formulations of up to two Genentech proteins, including hGH, utilizing Alkermes’ proprietary ProLease microencapsulation technology.