1420/GENENTECH
`
`Nutropin-Cont.
`
`Untreated hypothyroidism prevents optimal response to
`Nutropin. Patients with Turner syndrome have an inher~
`ently increased risk of developing autoimmune thyroid dis(cid:173)
`ease. Changes in thyroid hormone laboratory measure(cid:173)
`ments may develop during Nutropin treatment. 1'herefore,
`patients should have periodic thyroid function tests and
`should be treated with thyroid hormone when indicated.
`Drug Interactions: Excessive glucocorticoid therapy will
`inhibit the growth-promoting effect of human GH. Patients
`with ACTH deficiency should have their glucocorticoid-re(cid:173)
`placement dose carefully adjusted to avoid an inhibitory ef(cid:173)
`fect on growth.
`The use of Nutropin in patients with chronic renal insuffi(cid:173)
`ciency receiving glucocorticoid therapy has not been evalu(cid:173)
`ated. Concomitant glucocortlcoid therapy may inhibit the
`growth-promoting effect of Nutropin. If glucocorticoid-re(cid:173)
`placement is required, the glucocorticoid dose should be
`carefully adjusted.
`There was no evidence in the controlled studies of Nu(cid:173)
`tropin 's interaction with drugs commonly used in chronic re(cid:173)
`nal insufficiency patients. Limited published data indicate
`that GH treatment increases cytochrome P450 (CP450) me(cid:173)
`diated antipyrine clearance in man. These data suggest that
`GH administration may alter the clearance of compounds
`known to be metabolized by CP450 liver enzymes (e.g., cor(cid:173)
`ticosteroids, sex steroids, anticonvulsants, cyclosporin).
`Careful monitoring is advisable when GH is administered
`in combination with other drugs known to be metabolized
`by CP450 liver enzymes.
`Carcinogenesis, Mutagenesis, Impairment of Fertility: Car(cid:173)
`cinogenicity, mutagenicity, and reproduction studies have
`not been conducted with Nutropin.
`Pregnancy: Pregnancy (Category C). Animal reproduction
`studies have not been conducted with Nutropin. It is also
`not known whether Nutropin can cause fetal harm when ad(cid:173)
`ministered to a pregnant woman or can affect reproduction
`capacity. Nutropin should be given to a pregnant woman
`only if clearly needed.
`Nursing Mothers: It is not known whether Nutropin is ex(cid:173)
`creted in human mille Because many drugs are excreted in
`human milk, caution should be exercised when Nutropin is
`administered to a nursing mother.
`Information for Patients: Patients being treated with GH
`and/or their parents should be informed of the potential
`benefits and risks associated with treatment. If home use is
`determined to be desirable by the physician,·instructions on
`appropriate use ~hould be give'n, inclUding a review of the
`contents of the Patient Information Insert. This information
`is intended to aid in the safe and effective administratiori of
`the medication. It is not a disclosure of all possible ad.verse
`or intended effects.
`If home use is prescribed, a puncture-resistant container for
`the disposal of used syringes and needles should be recom(cid:173)
`mended to the patient. Patients and/or parents should be
`thoroughly instructed in the importance of proper disposal
`and cautioned against any reuse of needles and Syringes
`(see Patient Information Insert).
`
`ADVERSE REACTIONS
`As with all protein pharmaceuticals, a small percentage of
`patients may develop antibodies to the protein. GH anti(cid:173)
`body binding capacities below 2 mg!L have not been associ(cid:173)
`ated with growth attenuation. In some cases when binding
`capacity exceeds 2 mg/L, growth attenuation has been ob(cid:173)
`served. In clinical studies of pediatric patients that were
`treated with Nutropin for the first time, 0/107 growth hor(cid:173)
`mone-deficient (GHD) patients, 0/125 CRI patients, and
`0/112 Turner syndrome patients screened for antibody pro(cid:173)
`duction developed antibodies with binding capacities
`2:2 mg/L at six months.
`Additional short-term immunologic and renal function stud·
`ies were carried out in a group of patients with chronic renal
`insufficiency after approximately one year of treatment to
`detect other potential adverse effects of antibodies to GH.
`Testing included measurements of Clq, C3, C4, rheumatoid
`factor, creatinine, creatinine clearance, and BUN. No ad(cid:173)
`verse effects of GH antibodies were noted.
`In addition to an evaluation of compliance with the pre(cid:173)
`scribed treatment program and thyroid status, testing for
`antibodies to GH should be carried out in any patient who
`fails to respond to 'therapy.
`In studies in patients treated with Nutropin, injection site
`pain was reported infrequently.
`Leukemia has been reported in a small number of GHD pa(cid:173)
`tients treated with GH. It is uncertain whether this in(cid:173)
`creased risk is related to the pathology of GH deficiency it(cid:173)
`self, GH therapy, or other associated treatments such as ra(cid:173)
`diation therapy for intracranial tumors. On the basis of
`current evidence, experts cannot conclude that GH therapy
`is responsible for these occurrences. The risk to GHD, CRI,
`or Turner syndrome patients, if any; remains to be estab(cid:173)
`lished.
`Other adverse drug reactions that have been reported in
`GH-treated patients include the following: 1) Metabolic:
`mild, transient peripheral edema. In GHD adults, edema or
`peripheral edema was reported in 41% of GH-treated pa(cid:173)
`tients and 25% ofplacebo-treated patient..c;. 2) Musculoskele(cid:173)
`tal: arthralgias; carpal tunnel syndrome. In GHD adults, ar(cid:173)
`thralgias and other joint disorders were reported in 27% of
`GH-treated patients and 15% of placebo-treated patients. 3)
`
`Skin: rare increased growth of pre-existiJJ.g nevi; patients
`should be monitored for malignant transformation. 4) En(cid:173)
`docrine: gynecomastia. Rare pancreatitis.
`OVERDOSAGE
`Acute overdosage could lead to hyperglycemia. Long-term
`overdosage could result in signs and symptoms of gigantism
`andior acromegaly consistent with the known effects of ex(cid:173)
`cess GH. (See recommended and maximal dosage instruc(cid:173)
`tions given below.)
`DOSAGE AND ADMINISTRATION
`The Nutropin dosage and administration schedule should
`be individualized for each patient. Response to growth hor(cid:173)
`mone therapy in pediatric patients tends to decrease with
`time. However, in pediatric patients failure to increase
`growth._rate, particularly during the first year of therapy,
`suggests the need for close assessment of compliance and
`evaluation of other causes of growth failure, such as hypo(cid:173)
`thyroidism, under-nutrition, and advanced bone age.
`Dosage
`Pediatric Growth Hormone Deficiency (GHD)
`A weekly dosage of up to 0.30 mg!kg of body weight divided
`into daily subcutaneous injection is recommended. In puber(cid:173)
`tal patients, a weekly dosage of up to 0. 7 mg/kg divided
`daily may be used.
`Adult Growth Hortnone Deficiency (GHD)
`The recommended dosage at. the start of therapy is not more
`than 0.006 mglkg given as a daily subcutaneous injection.
`The dose may be increased according to individual patient
`requirements to a maximum of 0.025 mg/kg daily in pa(cid:173)
`tients under 35 years and to a maximum of 0.0125 mg!kg
`daily in patients over 35 years.
`To minimize the occurrenCe of adverse events .in older or
`overweight patients, lower doses may be necessary. During
`therapy, dosage should be decreased if required by the oc(cid:173)
`currence of side effects or excessive IGF-I levels.
`Chronic Rerial Insufficiency (CRI)
`A weekly dosage of up to 0.35 mg!kg of body weight divided
`into daily subcutaneous injection is recommended.
`Nutropin therapy may be continued up to the time of renal
`transplantation.
`In order to optimize therapy for patients who require dial(cid:173)
`ysis, the following guidelines for injection schedule are rec(cid:173)
`ommended:
`1. Hemodialysis patients should receive their .injection at
`night just prior to going to sleep or at least 3-4 hours
`after their hemodialysis to prevent hematoma formation
`due to the heparin.
`2. Chronic Cycling Peritoneal Dialysis (CCPD) patients
`should receive their injection in the morning after they
`have completed dialysis.
`3. Chronic Ambulatory Peritoneal Dialysis (CAPD) patients
`should receive their injection in the evening at the time of
`the overnight exchange.
`Turner Syndrome
`A weekly dosage of up to 0.375 mglkg of body weight divided
`into equal doses 3 to 7 times. per week by subcutaneous in(cid:173)
`jection is recommended.
`Administration
`After the dose has been determined, reconstitute as follows:
`each 5 mg vial should b~ reconstituted with 1-·5 mL of Bac(cid:173)
`teriostatic Water for Injection, USP (benzyl alcohol pre(cid:173)
`served); or each 10 mg vial should be reconstituted with
`1-10 mL of Bacteriostatic Water for Injection, USP (benzyl
`alcohol preserved), only. For use in newborn& see WARN(cid:173)
`INGS. The pH of Nutropin after reconstitution with Bacte(cid:173)
`riostatic Water for Injection, USP (benzyl alcohol pre~
`served), is approximately 7 .4.
`To prepare the Nutropin solution, inject the Bacteriostatic
`Water for Injection, USP (benzyl alcohol preserved), into the
`N utropin vial, aiming the stream of liquid against the glass
`wall. Then swirl the product vial with a GENTLE rotary mo(cid:173)
`tion until the contents are completely ·dissolved. DO NOT
`SHAKE. Because Nutropin is a protein, shaking can result
`in a cloudy solution. The Nutropin solution should be clear
`immediately after reconstitution. Occasionally, after refrig(cid:173)
`eration, you may notice that small colorless particles of pro(cid:173)
`tein are present in the Nutropin solution. This is not un(cid:173)
`usual for solutions containing proteins. If the solution is
`clOudy immediately after reconstitution or refrigeration, the
`contents MUST NOT be injected.
`Before needle insertion, wipe the septum of both the Nu(cid:173)
`tropin and diluent vials with rubbing alco!tol or an antisep~
`tic solution to prevent contamination of the contents by mi(cid:173)
`croorganisms that may be introduced by·repeated needle in(cid:173)
`sertions. It is recommended that Nutropin be administered
`using sterile, disposable syringes Md needles. The syringes
`should be of small enough volume that the prescribed. dose
`can be drawn from the vial with reasonable accuracy.
`STABILITY AND STORAGE
`Before Reconstitution-Nutropin® [somatropin (rDNA ori(cid:173)
`gin) for injection] and Bacteriostatic Water for Injection,
`USP (benzyl alcohol preserved), must be stored at 2-8'C/
`36--46.,F (under refrigeration). Avoid freezing the vials of
`Nutropin and Bacteriostatic Water for Injection, USP (ben(cid:173)
`zyl alcohol preserved). Expiration dates are stated on the
`labels.
`After Reconstitution-Vial contents are stable for 14 days
`when reconstituted with Bacteriostatic Water for Injection,
`USP (benzyl alcohol preserved), and stored at 2-8'C/36-
`46'F (under refrigeration). Store the unused portion ofBac·
`teriostatic Water for Injection, USP (benzyl alcohol pre(cid:173)
`served), at 2-8"C/36-4SOF (under refrigeration). Avoid
`
`PHYSICIANS' DESK REFERENCE®
`
`freezing the reconstituted vial of Nutropin and the Bacteri(cid:173)
`ostatic Water for Injection, USP (benzyl alcohol preserved).
`HOW SUPPLIED
`Nutropin is supplied as 5 mg (approximately 15 IU) or
`10 mg (approximately 30 IU) of lyophilized, sterile somatro(cid:173)
`pin per vial.
`Each 5 mg carton contains two vials of Nutropin® [somat(cid:173)
`ropin (rONA origin) for injection] (5 mg per vial) and one
`10 mL multiple dose vial of Bacteriostatic Water for Injec(cid:173)
`tion, USP (benzyl alcohol prese~ved). NDC 50242-072-02
`Each 10 mg catton contains two vials of Nutropin® {somat(cid:173)
`ropin (rDNA origin) for injection] (10 mg per vial) and two
`10 mL multiple dose vials of Bacteriostatic Water for Injec(cid:173)
`tion, USP (benzyl alcohol preserved).
`NDC 50242-018-20
`Nutropin® [somatropin (rDNA origin) for injection] manu(cid:173)
`factured by:
`Genenteth, Inc.
`1 DNA Way
`South San Francisco, CA 94080-4990
`Bacteriostatic Water for Injection, USP (benzyl
`alcohol preserved), manufactured for:
`Genentech, Inc.
`
`4808607
`Revised April 2000
`©2000 Genentech, Inc.
`Shown in Product Identification Guide, page 313
`
`NUTROPIN AQ®
`[somatropin (rONA origin} injection)
`
`DESCRIPTION
`Nutropin AQ® [somatropin (rDNA origin) injection] is a hu~
`man growth hormone (hGH) produced by recombinant DNA
`technology. Nutropin AQ has 191 amino acid residues and a
`molecular weight of 22,125 daltons. The amino acid se(cid:173)
`quence of the product is identical to that of pituitary-de(cid:173)
`rived human growth hormone. The protein is synthesized by
`a specific laboratory strain of E. coli as a precursor consist(cid:173)
`ing of the rhGH molecule preceded. by the secretion signal
`from an E. coli protein. This precursor is directed ·to the
`plasma membrane of the cell. The signal sequence is re(cid:173)
`moved and the native protein is secreted into the periplasm
`so that the protein is folded appropriately as it is synthe(cid:173)
`sized.
`Nutropin AQ·is a highly purified preparation. Biological po·
`tency is determined using a cell proliferation bioassay. Nu(cid:173)
`tropin AQ may contain not more than fifteen percent dea(cid:173)
`rnidatetl growth hormone (GH) at expiration. The deami(cid:173)
`dated form of GH has been extensively characterized and
`has been shown to be safe and fully active.
`Nutropin AQ is a sterile liquid intended for subcutaneous
`administration. The product is nearly isotonic at a concen(cid:173)
`tration of 5 mg of GH per mL and has a pH of approximately
`6.0.
`Each 2 mL vial contains 10 mg (approximately 30 IU) so·
`matropin, formulated in 17.4 mg sodium chloride, 5 mg phe(cid:173)
`nol, 4 mg polysorbate 20, and 10 mM sodium citrate.
`
`CLllnCALPHARMACOLOGY
`General
`In vitro and in vivo preclinical and clinical testing have
`demonstrated that Nutropin AQ is therapeutically equiva(cid:173)
`lent to pituitary-derived human GH (hGH). Pediatric pa(cid:173)
`tients who lack adequate endogenous GH secretion, pa(cid:173)
`tients with chronic renal insufficiency, and patients with
`'furner syndrome that were treated with Nutropin AQ or
`Nutropin® [somatropin (rDNA origin) for injection} resulted
`in an incr~ase iri growth rate and an increase in insulin-like
`growth factor-! (IGF-l) levels similar to that seen with pitu(cid:173)
`itary-derived hGH.
`Actions that have been demonstrated for Nutropin AQ, so(cid:173)
`matropin, somatrem, and/or pituitary-derived hGH include:
`A. Tissue Growth-1) Skeletal Growth: GH stimulates skel(cid:173)
`etal growth in pediatric patients with growth failure due
`to a lack of adequate secretion of endogenous GH or sec(cid:173)
`ondary to chronic renal insufficiency and in patients with
`Turner syndrome, Skeletal growth is accomplished at the
`epiphyseal plates at the ends of a growing bone. Growth
`and metabolism of epiphyseal plate cells are directly
`stlmulated by GH and one ofits meP.iators, IGF-L Serum
`levels of IGF-I are low in children and adolescents who
`are GH deficient, but increase during treatment with
`GH. In pediatric patients, new bone is formed at the
`epiphyses in response to GH and IGF-1. This results in
`linear growth until these growth plates fuse at the end of
`puberty. 2) Cell Growth: Treatment with hGH results in
`an increase in both the number and the size of skeletal
`muscle cells. 3) Organ Growth: GH influences the size of
`internal organs, including kidneys, and increases red cell
`mass. Treatment of hypophysectomized or genetic dwarf
`rats with GH results in organ growth that is proportional
`to the overall body growth. In normal rats subjected to
`nephrectomy-induced uremia, GH promoted skeletal and
`body growth.
`B. Protein Metabolism--Linear growth is facilitated in part
`by GH-stimulated protein synthesis. This is reflected by
`nitrogen retention as demonstrated by a decline in uri(cid:173)
`nary nitrogen excretion and blood urea nitrogen during
`GH therapy.
`
`Information will be superseded by supplements and subsequent edrtions
`
`Ex. 2041-0001
`
`

`
`PRODUCT INFORMATION
`
`GENENTECH/1421
`
`C. Carbohydrate Metabolism-GH is a modulator of carbo(cid:173)
`hydrate metabolism. For example, patients with inade·
`quate secretion of GH sometimes experience fasting hy(cid:173)
`poglycemia that is improved by treatment with GH. GH
`therapy may decrease insulin sensitivity. Untreated pa(cid:173)
`tients with chronic renal insufficiency and Turner syn(cid:173)
`drome have an increased incidence of glucose intoler(cid:173)
`ance. Administration of hGH to adults or children re(cid:173)
`sulted in increases in serum fasting and postprandial
`insulin levels, more commonly in overweight or obese in(cid:173)
`dividuals. In addition, mean fasting and postprandial
`glucose and hemoglobin A1c levels remained in the nor(cid:173)
`mal range.
`D. lipid Metabolism-In GH-deficient patients, administra(cid:173)
`tion of GH resulted in lipid mobilization, reduction in
`body fat stores, increased plasma fatty acids, and de(cid:173)
`creased plasma cholesterol levels.
`E. Mineral Metabolism-The retention of total body potas(cid:173)
`sium in response to GH administration apparently re(cid:173)
`sults from cellular growth. Serum levels of inorganic
`phosphorus may increase slightly in .Patients with inad(cid:173)
`equate secretion of endogenous GH, chronic renal insuf(cid:173)
`ficiency, or patients with Turner syndrome during GH
`therapy due to metabolic activity associated with bone
`growth as well as increased tubular reabsorption of phos(cid:173)
`phate by the kidney. Serum calcjum is not significantly
`altered in these patients. Sodium retention also occurs.
`Adults with childhood-onset GH deficiency show low
`bone mineral density (BMD). GH therapy results in in(cid:173)
`creases in serum alkaline phosphatase. (See PRECAU(cid:173)
`TIONS: Laboratory Tests.)
`F. Connective lissue Metabolism-GH stimulates the syn(cid:173)
`thesis of chondroitin sulfate and collagen as well as the
`urinary excretion of hydroxyproline.
`Pharmacokinetics
`Subcutaneous Absorption-The absolute bioavailability of
`recombinant human growth hormone (rhGH) after subcuta(cid:173)
`neous administration in healthy adult males has been de(cid:173)
`termined to be 81±20%. The mean terminal t 112·rafter sub(cid:173)
`cutaneous administration is significantly longer than th8.t
`seen after intravenous administration (2.1 :!:0.43 hr vs.
`19.5±3.1 min) indicating that the subcutaneous absorption
`of the compound is slow and rate-limiting.
`Distribution-Animal studies with rhGH showed that GH
`localizes to highly perfused organs, particularly the liver
`and kidney. The volume of distribution at steady state for
`rhGH in healthy adult males is about 50 mUkg body
`weight, approximating the serum volume.
`Metabolism-Both the liver and kidney have been shown to
`be important metabolizing organs for· GH. Animal studies
`suggest that the kidney is the dominant organ of clearance.
`GH is filtered at the glomerul:us and reabsor~ed iri·the prox(cid:173)
`imal tubules. It is then cleaved within renal cells into its
`eonstituent amino acids, which:return to the systemic circu(cid:173)
`lation.
`Elimination-The mean tenninal tm after intravenous ad(cid:173)
`ministration of rhGH in healthy adult males is estimated .to
`be 19.5:t:3.1 minutes .. Clearance of rhGH after intravenous
`administration in healthy adults and children is reported to
`be in the range of 116-174 mUhrlkg.
`Bioequivalence of Formulations-Nutropin AQ® [somatro(cid:173)
`pin (rDNA origin) injection] has been determined to be
`bioequivalent to Nutropin® [somatropin. (rDNA origin) for
`injection) based on the statistical evaluation of AUC and
`em,.·
`Special Populations
`Pediatric-Available literature data suggest that rhGH
`clearances are similar in adults and children.
`Gender-No data are available for exogenously adminis·
`tered rhGH. Available data for methionyl recombinant GH,
`pituitary-derived GH, and endogenous GH suggest no con(cid:173)
`sistent gender-based differences in GH clearance.
`Geriatrics-Limited published data suggest that the
`plasma clearance and average steady-state plasma concen(cid:173)
`tration of rhGH may not be different between young and el(cid:173)
`derly patients.
`Race-Reported values for half-lives for endogenous GH in
`normal adult black males are not different from observed
`values for normal adult white males. No data for other races
`are available.
`Growth Hormone Deficiency (GHD)-Reported values for
`clearance of rhGH in adults and children with GHD range
`138-245 mL/hrlkg and are similar to those observed in
`healthy adults and children. Mean terminal t 112 values fol·
`lowing intravenous and subcutaneous administration in
`adult and pediatric GHD patients are also similar to those
`observed in healthy adult males.
`Renal Insufficiency-Children and adults with chronic renal
`failure (CRF) and end-stage renal disease (ESRD) tend to
`have decreased clearance compared to nonnals. Endoge(cid:173)
`nous GH production may also increase in some individuals
`with ESRD. However, no rhGH accumulation has been re(cid:173)
`ported in children with CRF or ESRD dosed with current
`regimens.
`Turner Syndrome-No pharmacokinetic data are available
`for exogenously administered rhGH. However: reported
`half-Jives, absorption, and elimination rates for endogenous
`GH in this population are similar to the ranges observed for
`nonnal subjects and GHD populations.
`Hepatic Insufficiency--A reduction in rhGH clearance has
`been noted in patients with severe liver dysfunction. The
`clinical significance of this decrease is unknown.
`[See first table at top right!
`.
`[See figure at top of next column]
`
`Summary of Nutropin AQ Pharmacokinetic Parameters
`in Healthy Adult Males
`0.1 mg (approximately 0.3 IU')Ikg SC
`
`MEAN'
`CV%
`
`71.1
`17
`
`3.9
`56
`
`t._
`(hr)
`
`2.3
`18
`
`AUC.._,
`(pg•hr!L)
`
`677
`13
`
`CLIF,.
`(mU[hr•kg])
`
`150
`13
`
`Abbreviations: Cmax=maximum concentration; t 112 =half-life; AUC0.....,=area under the curve; CUF11c=systemic clearance;
`F se=subcutaneous bioavailability (not detennined); CV%=coefficient of variation in.%; SC=subcutaneous
`
`a Based on current International Standard of 3 IU=l .mg
`b n=36
`
`Last Measured Height* by Sex and Nutropin Dose
`
`Age (yr)
`Mean±SD (range)
`
`17.2±1.3
`(13.6 to 19.4)
`15.8±1.8
`(11.9 to 19.3)
`
`Last Measured Height* (em)
`0.3 mglkg/wk
`0.7 mg/kg/wk
`Mean.±:SD
`Meani.SD
`
`Between Groups (em)
`Mean±SE
`
`170.9±7.9
`(n=42)
`154.7±6.3
`(n=7)
`
`174.5±7.9
`(n=41)
`157.6±6.3
`(n=7)
`
`3.6±1.7
`
`2.9±3.4
`
`Male
`
`Female
`
`*Adjusted for baseline height
`
`Single Dose Mean Growth Hormone Concentrations
`in Healthv Adult Males
`1000 e----------------.,-,
`
`Mean±SE
`
`-·~- 0.10 mg/kg subcutaneous injection {n = 36)
`--o-- 0.02 mglkg Jntraveous InJection (n- 19)'
`
`i <:: 100
`
`g
`f!
`'E
`"
`" <::
`0
`()
`:r:
`(!)
`E
`2
`" (/)
`
`10
`
`1
`
`0.1
`
`0
`
`*1V somatropln concentration profll9
`Included for compaf1son
`
`12
`Time (hour) .,
`
`18
`
`24
`
`Efficacy Studies
`Growth Hormone Deficiency (GHDJ in Pubertal Patients
`One open-label, multicenter, randomized clinical tria1 of two
`dosages of Nutropin® [somatropin (rDNA origin) for injec(cid:173)
`tion! was performed in pubertal patients with GHD. Ninety(cid:173)
`seven patients (mean age 13.9 years, 83 male, 14 female)
`currently being treated with approximately 0.3 mg/kg/wk of
`GH were randomized to 0.3 mg/kg/wk or 0.7 mg/kg/wk Nu(cid:173)
`tropin doses. All patients were already in puberty (Tanner
`stage 2::2) and had bone ages :<S14 yr in males or s12 yr in
`females. Mean baseline height standard deviation (SD)
`score was -1.3.
`The mean last measured height in all 97 patients after a
`mean duration of 2. 7 .± 1.2 years, by analysis of covariance
`(ANCOVA) adjusting for baseline height, is shown below.
`[See second table above!
`The mean height SD score at last measured height (n=97)
`was -0.7±1.0 in the 0.3 mg/kg/wk group and -0.1±1.2 in
`the 0. 7 mg/kg/wk group. For patients completing 3.5 or
`more years (mean 4.1 years) of Nutropin treatment (15/49
`patients in the 0.3 mg/kglwk group and 16/48 patients in
`the 0.7 mg/kg!wk group), the mean last measured height
`was 166.1±8.0 em in the 0.3 mg/kg/wk group and 171:8±7.1
`em in the 0. 7 mg/kg/wk group, adjusting for baseline height
`and sex.
`The mean change in bone age was approximately one year
`for each year in the study in both dose groups. Patients with
`baseline height SD scores above -1.0 were able to S.ttain
`normal adult heights with the 0.3 mg/kg/wk dose of Nu(cid:173)
`tropin (mean height SO score at near-adult height = -0.1,
`n=15).
`Thirty-one patients had bone,mineral density (BMD) deter(cid:173)
`mined by dual energy x-ray absorptiometry (DEXA) scans
`at study conclusion. The two dose groups did not differ sig(cid:173)
`nificantly in mean SD score for total body BMD ( -0.9± 1.9
`in the 0.3 mg/kg/wkgroup vs. -0.8±1.2 in the 0.7 mg!kg/wk
`group, n=20) or lumbar spine BMD (-LO.tl.O in the 0.3 mg/
`kg/wk group vs. -0.2±1.7 in the 0.7 mg/kg/wk group, n=21).
`Over a mean duration of 2. 7 years, patients in the 0. 7 mg/
`kg/wk group were more likely to have IGF-1 values above
`the normal range than patients in the 0.3 mg/kglwk group
`(27.2% vs. 9.0% of IGF-1 measurements for individual pa(cid:173)
`tients). The clinical significance of elevated IGF-I values is
`unknown.
`Effects of Nutropin® [somatropin (rONA origin} for injec(cid:173)
`tion] on Growth Failure Due to Chronic Renal Insufficiency
`(CRll
`'1\vo multicenter, randomized, controlled clinical trials were
`conducted to determine whether treatment with Nutropin
`prior to renal transplantation in patients with chronic renal
`insufficiency could improve their growth rates and height
`deficits. One study was a double·blind, placebo-controlled
`trial and the other was an open-label, randomized trial. The
`dose of Nutropin in both controlled studies was 0.05 mg/kg/
`day (0.35 mg/kg/wk) administered daily by subcutaneous in·
`
`jection. Combining the data from those patients completing
`two years in the two controlled studies results in 62 patients
`treated with Nutropin and 28 patients in the control groups
`(either, placebo-treated or untreated). The mean first year
`growth rate was 10.8 cm/yr for Nutropin-treated patients,
`compared with a meaD. growth rate of 6.5 cmlyr for placebo
`untreated controls (p<0.00005). The mean second yea
`growth rate was 7.8 cnllyr for the Nutropin-treated group
`compared with 5.5 crnlyr for controls (p<0.00005). Ther
`was a significant increase in mean height standard devia
`tion (SO) score in the Nutropin group ( -2.9 at baseline to
`-1.5 at Month 24, n=62) but no significant change in th
`controls (- 2.8 at baseline to -2.9 at Month 24, n=28). Th
`mean ·third year growth rate of 7.6 crn/yr in the Nutropin
`treated patients (n=27) suggests that Nutropin stimulate
`growth beyond two years. However, there are no contra
`data for the third year because control patients crossed ave
`to Nutropin treatment after two years of participation. 'l'h
`gains in height were accompanied by appropriate advance
`ment of skeletal age. These data demonstrate that Nutropin
`therapy improves growth rate and corrects the acquired
`height deficit associated with chronic renal insufficiency.
`Currently there are insufficient data ~~t:~~~fit
`of treatment beyond three years. Alt~h predicted finai
`height was improved during Nutropin therap.Ir...!.he effect of
`Nutropin on final adult height remains to be determined.
`Post-Tran~plant Growth
`The North American Pediatric Renal Transplant Coopera
`tive Study (NAPRTCS) has reported data for growth post
`transplant in children who did not receive GH. The average
`change in height SD score during the initial two years post
`transplant was 0.18 (n=300, J Pediatr. 1993;122:397-402)
`Controlled studies of GH treatment for the short.stature as
`sociated with CRI were not designed to compare the growth
`of treated or untreated patients after they received renal
`transplants. However, growth data are available from a
`small number of patients who have been followed for at
`least 11 months. Of the 7 control patients, 4 increased their
`height SO score and 3 had eithei- no significant change or a
`decrease in height SD score. The 13 patients treated with
`Nutropin® {somatropin (rONA origin) for injection) prior to
`transplant had either no significant change or an increas
`in height SD score. after transplantation, indicating that th
`individual gains achieved with GH therapy prior to trans
`plant were maintained after transplantation. The diffe1
`ences in the height deficit narrowed between the treated
`and untreated groups in the post-transplant period.
`Turner Syndrome
`One long-term, randomized, open·label, multicenter, con
`currently controlled study, two long-term, open-label, mul(cid:173)
`ticenter, historically controlled studies and one long-term,
`randomized, dose-response study were conducted to evah
`ate the efficacy of GH for the treatment of girls with short
`stature due to Turner syndrome.
`In the randomized study GDCT, comparing GH-treated pa(cid:173)
`tients to a concurrent control group who received no GH, the
`GH·treated patients who received a dose of 0.3 mg/k:g/week
`given 6 times per week from a mean age of 11.7 years for a
`mean duration of 4. 7 years attained a mean near final
`height of 146.0 em tn=27) as compared to the control group
`who attained a near final height of 142.1 em (n=19). By
`analysis of covariance, the effect of GH therapy was a mean
`height increase of 5.4 em (p=O.OOI).
`In two of the studies (85-023 and 85-044), the effect of long(cid:173)
`term GH treatment (0.375 mg/kg/week given either 3 time
`per week or daily) on adult height was determined by com·
`paring adult heights in the treated patients with those of
`age-matched historical controls with Turner syndrome who
`never received any growth-promoting therapy. In Study 85-
`023, estrogen treatment was delayed until patients were at
`least age 14. GH therapy resulted in a mean adult height
`gain of 7.4 em (mean duration of 9-H therapy of 7.6 years)
`vs. matched historical controls by analysis of covariance.
`
`Continued on next page
`
`Consult 2 0 0 2 POR® supplements and future editions for revisions
`
`Ex. 2041-0002
`
`

`
`1422/GENENTECH
`
`Nutropin AO-Cont.
`
`In Study 85-044, patients treated with early GH therapy
`were randomized to receive estrogen-replacement therapy
`(conjugated estrogens, 0.3 mg escalating to 0.625 mg daily)
`at either age 12 or 15 years. Compared with matched his(cid:173)
`torical controls, early GH therapy (mean duration of GH
`therapy 5.6 years) combined with estrogen replacement at
`age 12 years resulted in an adult height gain of 5.9 em
`(n=26), whereas girls who initiated estrogen at age 15 years ·
`(mean duration of GH therapy 6.1 years) had a mean adult
`height gain of 8.3 em (n=29). Patients who initiated GH
`therapy after age 11 (mean age 12.7 years; mean duration of
`GH therapy 3.8 years) had a mean adult height gain of
`5.0 em (n=51)..
`Thus, in both studies, 85-023 and 85-044, the greatest im(cid:173)
`provement in adult height was observed. in patients-whore(cid:173)
`ceived early GH treatment and estrogen after age 14 years.
`In a randomized, blinded, dose-response study, GDCI, pa(cid:173)
`tients were treated from a mean age of 11.1 years for a
`mean duration of 5.3 years with a weekly dose of either
`0.27 mg!kg or 0.36 mglkg administered 3 or 6 times weekly.
`The mean near final height of patients receiving growth
`hormone was 148.7 em {n=31). This represents a mean gain
`in adult height of approximately 5 em compared with previ(cid:173)
`ous observations of untreated 'furner syndrome girls.
`In these studies, Turner syndr~me patients (n.=181) treated
`to final adult height achieved statistically significant aver(cid:173)
`age estimated adult height gains ranging 5.0-8.3 em.
`[See table at top right]
`Adult Growth Hormone Deficiency {GHDl
`Two multiceriter, double-blind, ·place~o-controlled. clinical
`trials were conducted using Nutropiri® [somatropin (rDNA
`origin) for injection] .in GH-deficient adults. One study was
`conducted in subjects with adult-onset GHD, mean age 48.3
`years, n=166, at doses of 0.0125 or 0.00625 mg/kg/day; doses
`of 0.025 mg/kg/day were not tolerated in these subjects. A
`second study was conducted in previously treated subjects
`with childhood-onset GHD, mean age 23.8 years, n=64, at
`randomly assigned doses of 0.025 or 0.0125 mg!kg/day. The
`studies were designed to assess the effects of replacement
`therapy with GH on body con:tposition.
`Significant changes from baseline to Month 12 of treatment
`in