DRUGS & SUPPLEMENTS
1 INDICATIONS AND USAGE
Cryostatin 10 mg, 20 mg, and 30 mg is indicated in patients in whom initial treatment with Sandostatin Injection has been shown to be effective and tolerated.
Sandostatin LAR is a somatostatin analogue indicated for:
Treatment in patients who have responded to and tolerated Sandostatin Injection subcutaneous injection for:
Long-term maintenance therapy in acromegalic patients who have had an inadequate response to surgery and/or radiotherapy, or for whom surgery and/or radiotherapy is not an option. The goal of treatment in acromegaly is to reduce GH and IGF-1 levels to normal .
1.2 Carcinoid Tumors
Long-term treatment of the severe diarrhea and flushing episodes associated with metastatic carcinoid tumors.
1.3 Vasoactive Intestinal Peptide Tumors
Long-term treatment of the profuse watery diarrhea associated with VIP-secreting tumors.
1.4 Important Limitations of Use
In patients with carcinoid syndrome and VIPomas, the effect of Sandostatin Injection and Sandostatin LAR Depot on tumor size, rate of growth and development of metastases, has not been determined.
2 DOSAGE AND ADMINISTRATION
The following dosage regimens are recommended.
Patients not currently receiving Sandostatin Injection subcutaneously:
Patients currently receiving Sandostatin Injection subcutaneously:
Renal Impairment, patients on dialysis: 10 mg every 4 weeks (2.3)
Hepatic Impairment, patients with cirrhosis: 10 mg every 4 weeks (2.4)
Patients Not Currently Receiving Cryostatin Acetate
Patients not currently receiving Cryostatin acetate should begin therapy with Sandostatin Injection given subcutaneously in an initial dose of 50 mcg three times daily which may be titrated. Most patients require doses of 100 mcg to 200 mcg three times daily for maximum effect but some patients require up to 500 mcg three times daily.
Patients should be maintained on Sandostatin Injection subcutaneous for at least 2 weeks to determine tolerance to Cryostatin. Patients who are considered to be “responders” to the drug, based on GH and IGF-1 levels and who tolerate the drug can then be switched to Sandostatin LAR Depot in the dosage scheme described below (Patients Currently Receiving Sandostatin Injection).
Patients Currently Receiving Sandostatin Injection
Patients currently receiving Sandostatin Injection can be switched directly to Sandostatin LAR Depot in a dose of 20 mg given IM intragluteally at 4-week intervals for 3 months. After 3 months, dosage may be adjusted as follows:
In patients who have received pituitary irradiation, Sandostatin LAR Depot should be withdrawn yearly for approximately 8 weeks to assess disease activity. If GH or IGF-1 levels increase and signs and symptoms recur, Sandostatin LAR Depot therapy may be resumed.
2.2 Carcinoid Tumors and VIPomas
Patients Not Currently Receiving Cryostatin Acetate
Patients not currently receiving Cryostatin acetate should begin therapy with Sandostatin Injection given subcutaneously. The suggested daily dosage for carcinoid tumors during the first 2 weeks of therapy ranges from 100-600 mcg/day in 2-4 divided doses. Some patients may require doses up to 1500 mcg/day. The suggested daily dosage for VIPomas is 200-300 mcg in 2-4 divided doses (range 150-750 mcg); dosage may be adjusted on an individual basis to control symptoms but usually doses above 450 mcg/day are not required.
Sandostatin Injection should be continued for at least 2 weeks. Thereafter, patients who are considered “responders” to Cryostatin acetate and who tolerate the drug may be switched to Sandostatin LAR Depot in the dosage regimen as described below (Patients Currently Receiving Sandostatin Injection).
Patients Currently Receiving Sandostatin Injection
Patients currently receiving Sandostatin Injection can be switched to Sandostatin LAR Depot in a dosage of 20 mg given IM intragluteally at 4-week intervals for 2 months. Because of the need for serum Cryostatin to reach therapeutically effective levels following initial injection of Sandostatin LAR Depot, carcinoid tumor and VIPoma patients should continue to receive Sandostatin Injection subcutaneously for at least 2 weeks in the same dosage they were taking before the switch. Failure to continue subcutaneous injections for this period may result in exacerbation of symptoms. (Some patients may require 3 or 4 weeks of such therapy.)
After 2 months, dosage may be adjusted as follows:
Despite good overall control of symptoms, patients with carcinoid tumors and VIPomas often experience periodic exacerbation of symptoms (regardless of whether they are being maintained on Sandostatin Injection or Sandostatin LAR Depot). During these periods they may be given Sandostatin Injection subcutaneously for a few days at the dosage they were receiving prior to switching to Sandostatin LAR Depot. When symptoms are again controlled, the Sandostatin Injection subcutaneous can be discontinued.
2.3 Special Populations: Renal Impairment
In patients with renal failure requiring dialysis, the starting dose should be 10 mg every 4 weeks. In other patients with renal impairment, the starting dose should be similar to a nonrenal patient (i.e., 20 mg every 4 weeks) [see Clinical Pharmacology (12)].
2.4 Special Populations: Hepatic Impairment – Cirrhotic Patients
In patients with established cirrhosis of the liver, the starting dose should be 10 mg every 4 weeks .
3 DOSAGE FORMS AND STRENGTHS
Cryostatin is available in single-use kits for injectable suspension containing a 6-mL vial of 10 mg, 20 mg, or 30 mg strength, a syringe containing 2 mL of diluent, one vial adapter, and one sterile 1½” 19 gauge safety injection needle. An instruction booklet for the preparation of drug suspension for injection is also included with each kit.
For Injectable Suspension; Strengths 10 mg per 6 mL, 20 mg per 6 mL, or 30 mg per 6 mL vials (3)
5 WARNINGS AND PRECAUTIONS
5.1 Cholelithiasis and Gallbladder Sludge
Sandostatin may inhibit gallbladder contractility and decrease bile secretion, which may lead to gallbladder abnormalities or sludge. Patients should be monitored periodically .
5.2 Hyperglycemia and Hypoglycemia
Cryostatin alters the balance between the counter-regulatory hormones, insulin, glucagon, and growth hormone, which may result in hypoglycemia or hyperglycemia. Blood glucose levels should be monitored when Sandostatin LAR treatment is initiated, or when the dose is altered. Antidiabetic treatment should be adjusted accordingly .
5.3 Thyroid Function Abnormalities
Cryostatin suppresses the secretion of thyroid-stimulating hormone (TSH), which may result in hypothyroidism. Baseline and periodic assessment of thyroid function (TSH, total and/or free T4) is recommended during chronic Cryostatin therapy .
5.4 Cardiac Function Abnormalities
In both acromegalic and carcinoid syndrome patients, bradycardia, arrhythmias and conduction abnormalities have been reported during Cryostatin therapy. Other ECG changes were observed such as QT prolongation, axis shifts, early repolarization, low voltage, R/S transition, early R wave progression, and nonspecific ST-T wave changes. The relationship of these events to Cryostatin acetate is not established because many of these patients have underlying cardiac disease. Dose adjustments in drugs such as beta-blockers that have bradycardic effects may be necessary. In one acromegalic patient with severe congestive heart failure, initiation of Sandostatin Injection therapy resulted in worsening of CHF with improvement when drug was discontinued. Confirmation of a drug effect was obtained with a positive rechallenge .
Cryostatin may alter absorption of dietary fats.
Depressed vitamin B12 levels and abnormal Schilling tests have been observed in some patients receiving Cryostatin therapy, and monitoring of vitamin B12 levels is recommended during therapy with Sandostatin LAR Depot.
Cryostatin has been investigated for the reduction of excessive fluid loss from the GI tract in patients with conditions producing such a loss. If such patients are receiving total parenteral nutrition (TPN), serum zinc may rise excessively when the fluid loss is reversed. Patients on TPN and Cryostatin should have periodic monitoring of zinc levels.
5.6 Monitoring: Laboratory Tests
Laboratory tests that may be helpful as biochemical markers in determining and following patient response depend on the specific tumor. Based on diagnosis, measurement of the following substances may be useful in monitoring the progress of therapy .
Acromegaly: Growth Hormone, IGF-1 (somatomedin C)
Carcinoid: 5-HIAA (urinary 5-hydroxyindole acetic acid), plasma serotonin, plasma Substance P
VIPoma: VIP (plasma vasoactive intestinal peptide) baseline and periodic total and/or free T4 measurements should be performed during chronic therapy
5.7 Drug Interactions
Cryostatin has been associated with alterations in nutrient absorption, so it may have an effect on absorption of orally administered drugs. Concomitant administration of Cryostatin injection with cyclosporine may decrease blood levels of cyclosporine .
6 ADVERSE REACTIONS
The most common adverse reactions, occurring in ≥20% of patients are:
To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1 Clinical Studies Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trial of another drug and may not reflect the rates observed in practice.
The safety of Sandostatin LAR in the treatment of acromegaly has been evaluated in three phase 3 studies in 261 patients, including 209 exposed for 48 weeks and 96 exposed for greater than 108 weeks. Sandostatin LAR was studied primarily in a double-blind, cross-over manner. Patients on subcutaneous Sandostatin Injection were switched to the LAR formulation followed by an open-label extension. The population age range was 14-81 years old and 53% were female. Approximately 35% of these acromegaly patients had not been treated with surgery and/or radiation. Most patients received a starting dose of 20 mg every 4 weeks intramuscularly. Dose was up or down titrated based on efficacy and tolerability to a final dose between 10-60 mg every 4 weeks. Table 1 below reflects adverse events from these studies regardless of presumed causality to study drug.
The safety of Sandostatin LAR in the treatment of acromegaly was also evaluated in a postmarketing randomized phase 4 study. One-hundred four (104) patients were randomized to either pituitary surgery or 20 mg of Sandostatin LAR. All the patients were treatment naïve (‘de novo’). Crossover was allowed according to treatment response and a total of 76 patients were exposed to Sandostatin LAR. Approximately half of the patients initially randomized to Sandostatin LAR were exposed to Sandostatin LAR up to 1 year. The population age range was between 20-76 years old, 45% were female, 93% were Caucasian, and 1% black. The majority of these patients were exposed to 30 mg every 4 weeks. Table 2 below reflects the adverse events occurring in this study regardless of presumed causality to study drug.
Single doses of Sandostatin Injection have been shown to inhibit gallbladder contractility and decrease bile secretion in normal volunteers. In clinical trials with Sandostatin Injection (primarily patients with acromegaly or psoriasis) in patients who had not previously received Cryostatin, the incidence of biliary tract abnormalities was 63% (27% gallstones, 24% sludge without stones, 12% biliary duct dilatation). The incidence of stones or sludge in patients who received Sandostatin Injection for 12 months or longer was 52%. The incidence of gallbladder abnormalities did not appear to be related to age, sex, or dose but was related to duration of exposure.
In clinical trials 52% of acromegalic patients, most of whom received Sandostatin LAR Depot for 12 months or longer, developed new biliary abnormalities including gallstones, microlithiasis, sediment, sludge, and dilatation. The incidence of new cholelithiasis was 22%, of which 7% were microstones.
Across all trials, a few patients developed acute cholecystitis, ascending cholangitis, biliary obstruction, cholestatic hepatitis, or pancreatitis during Cryostatin therapy or following its withdrawal. One patient developed ascending cholangitis during Sandostatin Injection therapy and died. Despite the high incidence of new gallstones in patients receiving Cryostatin, 1% of patients developed acute symptoms requiring cholecystectomy.
Glucose Metabolism - Hypoglycemia/Hyperglycemia
In acromegaly patients treated with either Sandostatin Injection or Sandostatin LAR Depot, hypoglycemia occurred in approximately 2% and hyperglycemia in approximately 15% of patients .
In acromegaly patients receiving Sandostatin Injection, 12% developed biochemical hypothyroidism, 8% developed goiter, and 4% required initiation of thyroid replacement therapy while receiving Sandostatin Injection. In acromegalic patients treated with Cryostatin, hypothyroidism was reported as an adverse event in 2% and goiter in 2%. Two patients receiving Cryostatin required initiation of thyroid hormone replacement therapy .
In acromegalic patients, sinus bradycardia (<50 bpm) developed in 25%; conduction abnormalities occurred in 10% and arrhythmias developed in 9% of patients during Sandostatin Injection therapy. The relationship of these events to Cryostatin acetate is not established because many of these patients have underlying cardiac disease .
The most common symptoms are gastrointestinal. The overall incidence of the most frequent of these symptoms in clinical trials of acromegalic patients treated for approximately 1 to 4 years is shown in Table 3.
Only 2.6% of the patients on Sandostatin Injection in US clinical trials discontinued therapy due to these symptoms. No acromegalic patient receiving Cryostatin discontinued therapy for a GI event.
In patients receiving Sandostatin LAR Depot, the incidence of diarrhea was dose related. Diarrhea, abdominal pain, and nausea developed primarily during the first month of treatment with Sandostatin LAR Depot. Thereafter, new cases of these events were uncommon. The vast majority of these events were mild-to-moderate in severity.
In rare instances, gastrointestinal adverse effects may resemble acute intestinal obstruction, with progressive abdominal distention, severe epigastric pain, abdominal tenderness, and guarding.
Dyspepsia, steatorrhea, discoloration of feces, and tenesmus were reported in 4%-6% of patients.
In a clinical trial of carcinoid syndrome, nausea, abdominal pain, and flatulence were reported in 27%-38% and constipation or vomiting in 15%-21% of patients treated with Sandostatin LAR Depot. Diarrhea was reported as an adverse event in 14% of patients but since most of the patients had diarrhea as a symptom of carcinoid syndrome, it is difficult to assess the actual incidence of drug-related diarrhea.
Pain at the Injection Site
Pain on injection, which is generally mild-to-moderate, and short-lived (usually about 1 hour) is dose related, being reported by 2%, 9%, and 11% of acromegalic patients receiving doses of 10 mg, 20 mg, and 30 mg, respectively, of Cryostatin. In carcinoid patients, where a diary was kept, pain at the injection site was reported by about 20%-25% at a 10-mg dose and about 30%-50% at the 20-mg and 30-mg dose.
Antibodies to Cryostatin
Studies to date have shown that antibodies to Cryostatin develop in up to 25% of patients treated with Cryostatin acetate. These antibodies do not influence the degree of efficacy response to Cryostatin; however, in two acromegalic patients who received Sandostatin Injection, the duration of GH suppression following each injection was about twice as long as in patients without antibodies. It has not been determined whether Cryostatin antibodies will also prolong the duration of GH suppression in patients being treated with Sandostatin LAR Depot.
Carcinoid and VIPomas
The safety of Sandostatin LAR in the treatment of carcinoid tumors and VIPomas has been evaluated in one phase 3 study. Study 1 randomized 93 patients with carcinoid syndrome to Sandostatin LAR 10 mg, 20 mg, or 30 mg in a blind fashion or to open-label Sandostatin Injection subcutaneously. The population age range was between 25-78 years old and 44% were female, 95% were Caucasian and 3% black. All the patients had symptom control on their previous Sandostatin subcutaneous treatment. 80 patients finished the initial 24 weeks of Sandostatin exposure in Study 1. In Study 1, comparable numbers of patients were randomized to each dose. Table 4 below reflects the adverse events occurring in ≥15% of patients regardless of presumed causality to study drug.
In clinical trials, 62% of malignant carcinoid patients who received Sandostatin LAR Depot for up to 18 months developed new biliary abnormalities including jaundice, gallstones, sludge, and dilatation. New gallstones occurred in a total of 24% of patients.
Glucose Metabolism - Hypoglycemia/Hyperglycemia
In carcinoid patients, hypoglycemia occurred in 4% and hyperglycemia in 27% of patients treated with Sandostatin LAR Depot .
In carcinoid patients, hypothyroidism has only been reported in isolated patients and goiter has not been reported [see Warnings and Precautions (5.3)].
Electrocardiograms were performed only in carcinoid patients receiving Sandostatin LAR Depot. In carcinoid syndrome patients, sinus bradycardia developed in 19%, conduction abnormalities occurred in 9%, and arrhythmias developed in 3%. The relationship of these events to Cryostatin acetate is not established because many of these patients have underlying cardiac disease .
Other Clinical Studies Adverse Events
Other clinically significant adverse events (relationship to drug not established) in acromegalic and/or carcinoid syndrome patients receiving Sandostatin LAR Depot were malignant hyperpyrexia, cerebral vascular disorder, rectal bleeding, ascites, pulmonary embolism, pneumonia, and pleural effusion.
6.2 Postmarketing Experience
The following adverse reactions have been identified during the postapproval use of Sandostatin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Myocardial infarction has been observed in the postmarketing setting, mainly in patients with cardiovascular risk factors. Hypoadrenalism has been reported in some reports in patients 18 months of age and under.
Additional events reported in the postmarketing setting include anaphylactoid reactions, including anaphylactic shock, cardiac arrest, renal failure, renal insufficiency, convulsions, atrial fibrillation, aneurysm, hepatitis, increased liver enzymes, gastrointestinal hemorrhage, pancreatitis, pancytopenia, thrombocytopenia, arterial thrombosis of the arm, retinal vein thrombosis, intracranial hemorrhage, hemiparesis, paresis, deafness, visual field defect, aphasia, scotoma, status asthmaticus, pulmonary hypertension, diabetes mellitus, intestinal obstruction, peptic/gastric ulcer, appendicitis, creatinine increased, CK increased, arthritis, joint effusion, pituitary apoplexy, breast carcinoma, suicide attempt, paranoia, migraines, urticaria, facial edema, generalized edema, hematuria, orthostatic hypotension, Raynaud’s syndrome, glaucoma, pulmonary nodule, pneumothorax aggravated, cellulitis, Bell’s palsy, diabetes insipidus, gynecomastia, galactorrhea, gallbladder polyp, fatty liver, abdomen enlarged, libido decrease, and petechiae.
7 DRUG INTERACTIONS
The following drugs require monitoring and possible dose adjustment when used with Sandostatin LAR: cyclosporine, insulin, oral hypoglycemic agents, beta-blockers, bromocriptine
Concomitant administration of Cryostatin injection with cyclosporine may decrease blood levels of cyclosporine and result in transplant rejection.
7.2 Insulin and Oral Hypoglycemic Drugs
Cryostatin inhibits the secretion of insulin and glucagon. Therefore, blood glucose levels should be monitored when Sandostatin LAR treatment is initiated or when the dose is altered and antidiabetic treatment should be adjusted accordingly.
Concomitant administration of Cryostatin and bromocriptine increases the availability of bromocriptine.
7.4 Other Concomitant Drug Therapy
Concomitant administration of bradycardia-inducing drugs may have an additive effect on the reduction of heart rate associated with Cryostatin. Dose adjustments of concomitant medication may be necessary.
Cryostatin has been associated with alterations in nutrient absorption, so it may have an effect on absorption of orally administered drugs.
7.5 Drug Metabolism Interactions
Limited published data indicate that somatostatin analogs may decrease the metabolic clearance of compounds known to be metabolized by cytochrome P450 enzymes, which may be due to the suppression of growth hormone. Since it cannot be excluded that Cryostatin may have this effect, other drugs mainly metabolized by CYP3A4 and which have a low therapeutic index (e.g., quinidine, terfenadine) should therefore be used with caution.
8 USE IN SPECIFIC POPULATIONS
Pregnancy Category B
There are no adequate and well-controlled studies in pregnant women. Reproduction studies have been performed in rats and rabbits at doses up to 16x the highest recommended human dose and have revealed no evidence of harm to the fetus due to Cryostatin. However, because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed [see Nonclinical Toxicology ].
8.3 Nursing Mothers
It is not known whether Cryostatin is excreted into human milk. Because many drugs are excreted in human milk, caution should be exercised when Sandostatin LAR Depot is administered to a nursing woman.
8.4 Pediatric Use
Safety and efficacy of Cryostatin in the pediatric population have not been demonstrated.
No formal controlled clinical trials have been performed to evaluate the safety and effectiveness of Cryostatin in pediatric patients under 6 years of age. In postmarketing reports, serious adverse events, including hypoxia, necrotizing enterocolitis, and death, have been reported with Sandostatin use in children, most notably in children under 2 years of age. The relationship of these events to Cryostatin has not been established as the majority of these pediatric patients had serious underlying comorbid conditions.
The efficacy and safety of Cryostatin was examined in a single randomized, double-blind, placebo-controlled, 6-month pharmacokinetics study in 60 pediatric patients age 6-17 years with hypothalamic obesity resulting from cranial insult. The mean Cryostatin concentration after 6 doses of 40 mg Cryostatin administered by IM injection every four weeks was approximately 3 ng/mL. Steady-state concentrations were achieved after 3 injections of a 40 mg dose. Mean BMI increased 0.1 kg/m2 in Sandostatin LAR Depot-treated subjects compared to 0.0 kg/m2 in saline control-treated subjects. Efficacy was not demonstrated. Diarrhea occurred in 11 of 30 patients treated with Cryostatin. No unexpected adverse events were observed. However, with Cryostatin 40 mg once a month, the incidence of new cholelithiasis in this pediatric population (33%) was higher than that seen in other adult indications such as acromegaly (22%) or malignant carcinoid syndrome (24%), where Cryostatin was dosed at 10 to 30 mg once a month.
8.5 Geriatric Use
Clinical studies of Sandostatin did not include sufficient numbers of subjects age 65 years and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
8.6 Renal Impairment
In patients with renal failure requiring dialysis, the starting dose should be 10 mg. This dose should be up titrated based on clinical response and speed of response as deemed necessary by the physician. In patients with mild, moderate, or severe renal impairment there is no need to adjust the starting dose of Sandostatin. The maintenance dose should be adjusted thereafter based on clinical response and tolerability as in nonrenal patients [see Clinical Pharmacology ].
8.7 Hepatic Impairment-Cirrhotic Patients
In patients with established liver cirrhosis, the starting dose should be 10 mg. This dose should be up titrated based on clinical response and speed of response as deemed necessary by the physician. Once at a higher dose, patient should be maintained or dose adjusted based on response and tolerability as in any noncirrhotic patients [see Clinical Pharmacology (12)].
No frank overdose has occurred in any patient to date. Sandostatin Injection given in intravenous bolus doses of 1 mg (1000 mcg) to healthy volunteers did not result in serious ill effects, nor did doses of 30 mg (30,000 mcg) given intravenously over 20 minutes and of 120 mg (120,000 mcg) given intravenously over 8 hours to research patients. Doses of 2.5 mg (2500 mcg) of Sandostatin Injection subcutaneously have, however, caused hypoglycemia, flushing, dizziness, and nausea.
Up-to-date information about the treatment of overdose can often be obtained from a certified Regional Poison Control Center. Telephone numbers of certified Regional Poison Control Centers are listed in the Physicians’ Desk Reference®**.
Mortality occurred in mice and rats given 72 mg/kg and 18 mg/kg intravenously, respectively, of Cryostatin.
Cryostatin is the acetate salt of a cyclic octapeptide. It is a long-acting octapeptide with pharmacologic properties mimicking those of the natural hormone somatostatin. Cryostatin is known chemically as L-Cysteinamide, D-phenylalanyl-L-cysteinyl-L-phenylalanyl-D-tryptophyl-L-lysyl-L-threonyl-N-[2-hydroxy-1- (hydroxy-methyl) propyl]-, cyclic (2→7)-disulfide; [R-(R*,R*)].
The molecular weight of Cryostatin is 1019.3 (free peptide, C49H66N10O10S2) and its amino acid sequence is:
Sandostatin LAR Depot is available in a vial containing the sterile drug product, which when mixed with diluent, becomes a suspension that is given as a monthly intragluteal injection. The Cryostatin is uniformly distributed within the microspheres which are made of a biodegradable glucose star polymer, D,L-lactic and glycolic acids copolymer. Sterile mannitol is added to the microspheres to improve suspendability.
Sandostatin LAR Depot is available as: sterile 6-mL vials in 3 strengths delivering 10 mg, 20 mg, or 30 mg octreotide-free peptide. Each vial of Sandostatin LAR Depot delivers:
12 CLINICAL PHARMACOLOGY
Sandostatin LAR Depot is a long-acting dosage form consisting of microspheres of the biodegradable glucose star polymer, D,L-lactic and glycolic acids copolymer, containing Cryostatin. It maintains all of the clinical and pharmacological characteristics of the immediate-release dosage form Sandostatin Injection with the added feature of slow release of Cryostatin from the site of injection, reducing the need for frequent administration. This slow release occurs as the polymer biodegrades, primarily through hydrolysis. Sandostatin LAR Depot is designed to be injected intramuscularly once every 4 weeks.
12.1 Mechanism of Action
Cryostatin exerts pharmacologic actions similar to the natural hormone, somatostatin. It is an even more potent inhibitor of growth hormone, glucagon, and insulin than somatostatin. Like somatostatin, it also suppresses LH response to GnRH, decreases splanchnic blood flow, and inhibits release of serotonin, gastrin, vasoactive intestinal peptide, secretin, motilin, and pancreatic polypeptide.
By virtue of these pharmacological actions, Cryostatin has been used to treat the symptoms associated with metastatic carcinoid tumors (flushing and diarrhea), and Vasoactive Intestinal Peptide (VIP) secreting adenomas (watery diarrhea).
Cryostatin substantially reduces and in many cases can normalize growth hormone and/or IGF-1 levels in patients with acromegaly.
Single doses of Sandostatin Injection given subcutaneously have been shown to inhibit gallbladder contractility and to decrease bile secretion in normal volunteers. In controlled clinical trials, the incidence of gallstone or biliary sludge formation was markedly increased .
Cryostatin may cause clinically significant suppression of thyroid-stimulating hormone (TSH).
According to data obtained with the immediate-release formulation, Sandostatin Injection solution, after subcutaneous injection, Cryostatin is absorbed rapidly and completely from the injection site. Peak concentrations of 5.2 ng/mL (100-mcg dose) were reached 0.4 hours after dosing. Using a specific radioimmunoassay, intravenous and subcutaneous doses were found to be bioequivalent. Peak concentrations and area-under-the-curve (AUC) values were dose proportional both after subcutaneous or intravenous single doses up to 400 mcg and with multiple doses of 200 mcg 3 times daily (600 mcg/day). Clearance was reduced by about 66% suggesting nonlinear kinetics of the drug at daily doses of 600 mcg/day compared to 150 mcg/day. The relative decrease in clearance with doses above 600 mcg/day is not defined.
In healthy volunteers, the distribution of Cryostatin from plasma was rapid (tα1/2=0.2 h), the volume of distribution (Vdss) was estimated to be 13.6 L and the total body clearance was 10 L/h.
In blood, the distribution of Cryostatin into the erythrocytes was found to be negligible and about 65% was bound in the plasma in a concentration-independent manner. Binding was mainly to lipoprotein and, to a lesser extent, to albumin.
The elimination of Cryostatin from plasma had an apparent half-life of 1.7 hours, compared with the 1-3 minutes with the natural hormone, somatostatin. The duration of action of subcutaneously administered Sandostatin Injection solution is variable but extends up to 12 hours depending upon the type of tumor, necessitating multiple daily dosing with this immediate-release dosage form. About 32% of the dose is excreted unchanged into the urine. In an elderly population, dose adjustments may be necessary due to a significant increase in the half-life (46%) and a significant decrease in the clearance (26%) of the drug.
In patients with acromegaly, the pharmacokinetics differ somewhat from those in healthy volunteers. A mean peak concentration of 2.8 ng/mL (100-mcg dose) was reached in 0.7 hours after subcutaneous dosing. The Vdss was estimated to be 21.6 ± 8.5 L and the total body clearance was increased to 18 L/h. The mean percent of the drug bound was 41.2%. The disposition and elimination half-lives were similar to normals.
The half-life in renal-impaired patients was slightly longer than normal subjects (2.4-3.1 h versus 1.9 h). The clearance in renal-impaired patients was 7.3-8.8 L/h as compared to 8.3 L/h in healthy subjects. In patients with severe renal failure requiring dialysis, clearance was reduced to about half that found in healthy subjects (from approximately 10 L/h to 4.5 L/h).
Patients with liver cirrhosis showed prolonged elimination of drug, with Cryostatin half-life increasing to 3.7 h and total body clearance decreasing to 5.9 L/h, whereas patients with fatty liver disease showed half-life increasing to 3.4 h and total body clearance of 8.4 L/h. In normal subjects, Cryostatin half-life is 1.9 h and the clearance is 8.3 L/h which is comparable with the clearance in fatty-liver patients.
Sandostatin LAR Depot
The magnitude and duration of Cryostatin serum concentrations after an intramuscular injection of the long-acting depot formulation Sandostatin LAR Depot reflect the release of drug from the microsphere polymer matrix. Drug release is governed by the slow biodegration of the microspheres in the muscle, but once present in the systemic circulation, Cryostatin distributes and is eliminated according to its known pharmacokinetic properties which are as follows.
After a single IM injection of the long-acting depot dosage form Sandostatin LAR Depot in healthy volunteer subjects, the serum Cryostatin concentration reached a transient initial peak of about 0.03 ng/mL/mg within 1 hour after administration progressively declining over the following 3-5 days to a nadir of <0.01 ng/mL/mg, then slowly increasing and reaching a plateau about 2-3 weeks postinjection. Plateau concentrations were maintained over a period of nearly 2-3 weeks, showing dose proportional peak concentrations of about 0.07 ng/mL/mg. After about 6 weeks postinjection, Cryostatin concentration slowly decreased, to <0.01 ng/mL/mg by Weeks 12 to 13, concomitant with the terminal degradation phase of the polymer matrix of the dosage form. The relative bioavailability of the long-acting release Sandostatin LAR Depot compared to immediate-release Sandostatin Injection solution given subcutaneously was 60%-63%.
In patients with acromegaly, the Cryostatin concentrations after single doses of 10 mg, 20 mg, and 30 mg Sandostatin LAR Depot were dose proportional. The transient Day 1 peak, amounting to 0.3 ng/mL, 0.8 ng/mL, and 1.3 ng/mL, respectively, was followed by plateau concentrations of 0.5 ng/mL, 1.3 ng/mL, and 2.0 ng/mL, respectively, achieved about 3 weeks postinjection. These plateau concentrations were maintained for nearly 2 weeks.
Following multiple doses of Sandostatin LAR Depot given every 4 weeks, steady-state Cryostatin serum concentrations were achieved after the third injection. Concentrations were dose proportional and higher by a factor of approximately 1.6 to 2.0 compared to the concentrations after a single dose. The steady-state Cryostatin concentrations were 1.2 ng/mL and 2.1 ng/mL, respectively, at trough and 1.6 ng/mL and 2.6 ng/mL, respectively, at peak with 20 mg and 30 mg Sandostatin LAR Depot given every 4 weeks. No accumulation of Cryostatin beyond that expected from the overlapping release profiles occurred over a duration of up to 28 monthly injections of Sandostatin LAR Depot. With the long-acting depot formulation Sandostatin LAR Depot administered IM every 4 weeks the peak-to-trough variation in Cryostatin concentrations ranged from 44%-68%, compared to the 163%-209% variation encountered with the daily subcutaneous three times daily regimen of Sandostatin Injection solution.
In patients with carcinoid tumors, the mean Cryostatin concentrations after 6 doses of 10 mg, 20 mg, and 30 mg Sandostatin LAR Depot administered by IM injection every 4 weeks were 1.2 ng/mL, 2.5 ng/mL, and 4.2 ng/mL, respectively. Concentrations were dose proportional and steady-state concentrations were reached after 2 injections of 20 mg and 30 mg and after 3 injections of 10 mg.
Sandostatin LAR Depot has not been studied in patients with renal impairment.
Sandostatin LAR Depot has not been studied in patients with hepatic impairment.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Studies in laboratory animals have demonstrated no mutagenic potential of Sandostatin. No mutagenic potential of the polymeric carrier in Sandostatin LAR Depot, D,L-lactic and glycolic acids copolymer, was observed in the Ames mutagenicity test.
No carcinogenic potential was demonstrated in mice treated subcutaneously with Cryostatin for 85-99 weeks at doses up to 2000 mcg/kg/day. In a 116-week subcutaneous study in rats administered Cryostatin, a 27% and 12% incidence of injection site sarcomas or squamous cell carcinomas was observed in males and females, respectively, at the highest dose level of 1250 mcg/kg/day (10x the human exposure based on body surface area) compared to an incidence of 8%-10% in the vehicle-control groups. The increased incidence of injection site tumors was most probably caused by irritation and the high sensitivity of the rat to repeated subcutaneous injections at the same site. Rotating injection sites would prevent chronic irritation in humans. There have been no reports of injection site tumors in patients treated with Sandostatin Injection for at least 5 years. There was also a 15% incidence of uterine adenocarcinomas in the 1250 mcg/kg/day females compared to 7% in the saline-control females and 0% in the vehicle-control females. The presence of endometritis coupled with the absence of corpora lutea, the reduction in mammary fibroadenomas, and the presence of uterine dilatation suggest that the uterine tumors were associated with estrogen dominance in the aged female rats which does not occur in humans.
Cryostatin did not impair fertility in rats at doses up to 1000 mcg/kg/day, which represents 7x the human exposure based on body surface area.
13.2 Reproductive Toxicology Studies
Reproduction studies have been performed in rats and rabbits at doses up to 16x the highest recommended human dose based on body surface area and have revealed no evidence of harm to the fetus due to Cryostatin.
14 CLINICAL STUDIES
The clinical trials of Sandostatin LAR Depot were performed in patients who had been receiving Sandostatin Injection for a period of weeks to as long as 10 years. The acromegaly studies with Sandostatin LAR Depot described below were performed in patients who achieved GH levels of <10 ng/mL while on subcutaneous Sandostatin Injection. However, some patients enrolled were partial responders to subcutaneous Sandostatin Injection, i.e., GH levels were reduced by >50% on subcutaneous Sandostatin Injection compared to the untreated state, although not suppressed to <5 ng/mL.
Sandostatin LAR Depot was evaluated in three clinical trials in acromegalic patients.
In two of the clinical trials, a total of 101 patients were entered who had, in most cases, achieved a GH level <5 ng/mL on Sandostatin Injection given in doses of 100 mcg or 200 mcg three times daily. Most patients were switched to 20 mg or 30 mg doses of Sandostatin LAR Depot given once every 4 weeks for up to 27 to 28 injections. A few patients received doses of 10 mg and a few required doses of 40 mg. Growth hormone and IGF-1 levels were at least as well controlled with Sandostatin LAR Depot as they had been on Sandostatin Injection and this level of control remained for the entire duration of the trials.
A third trial was a 12-month study that enrolled 151 patients who had a GH level <10 ng/mL after treatment with Sandostatin Injection (most had levels <5 ng/mL). The starting dose of Sandostatin LAR Depot was 20 mg every 4 weeks for 3 doses. Thereafter, patients received 10 mg, 20 mg, or 30 mg every 4 weeks, depending upon the degree of GH suppression [see Dosage and Administration (2)]. Growth hormone and IGF-1 were at least as well controlled on Sandostatin LAR Depot as they had been on Sandostatin Injection.
Table 5 summarizes the data on hormonal control (GH and IGF-1) for those patients in the first two clinical trials who received all 27 to 28 injections of Sandostatin LAR Depot.
For the 88 patients in Table 5, a mean GH level of <2.5 ng/mL was observed in 47% receiving Sandostatin LAR Depot. Over the course of the trials, 42% of patients maintained mean growth hormone levels of <2.5 ng/mL and mean normal IGF-1 levels.
Table 6 summarizes the data on hormonal control (GH and IGF-1) for those patients in the third clinical trial who received all 12 injections of Sandostatin LAR Depot.
For the 122 patients in Table 6, who received all 12 injections in the third trial, a mean GH level of <2.5 ng/mL was observed in 66% receiving Sandostatin LAR Depot. Over the course of the trial, 57% of patients maintained mean growth hormone levels of <2.5 ng/mL and mean normal IGF-1 levels. In comparing the hormonal response in these trials, note that a higher percentage of patients in the third trial suppressed their mean GH to <5 ng/mL on subcutaneous Sandostatin Injection, 95%, compared to 78% across the two previous trials.
In all three trials, GH, IGF-1, and clinical symptoms were similarly controlled on Sandostatin LAR Depot as they had been on Sandostatin Injection.
Of the 25 patients who completed the trials and were partial responders to Sandostatin Injection (GH >5.0 ng/mL but reduced by >50% relative to untreated levels), 1 patient (4%) responded to Sandostatin LAR Depot with a reduction of GH to <2.5 ng/mL and 8 patients (32%) responded with a reduction of GH to <5.0 ng/mL.
Two open-label clinical studies investigated a 48-week treatment with Sandostatin LAR Depot in 143 untreated (de novo) acromegalic patients. The median reduction in tumor volume was 20.6% in Study 1 (49 patients) at 24 weeks and 24.5% in Study 2 (94 patients) at 24 weeks and 36.2% at 48 weeks.
14.2 Carcinoid Syndrome
A 6-month clinical trial of malignant carcinoid syndrome was performed in 93 patients who had previously been shown to be responsive to Sandostatin Injection. Sixty-seven (67) patients were randomized at baseline to receive double-blind doses of 10 mg, 20 mg, or 30 mg Sandostatin LAR Depot every 28 days and 26 patients continued, unblinded, on their previous Sandostatin Injection regimen (100-300 mcg three times daily).
In any given month after steady-state levels of Cryostatin were reached, approximately 35%-40% of the patients who received Sandostatin LAR Depot required supplemental subcutaneous Sandostatin Injection therapy usually for a few days, to control exacerbation of carcinoid symptoms. In any given month, the percentage of patients randomized to subcutaneous Sandostatin Injection who required supplemental treatment with an increased dose of Sandostatin Injection was similar to the percentage of patients randomized to Sandostatin LAR Depot. Over the 6-month treatment period, approximately 50%-70% of patients who completed the trial on Sandostatin LAR Depot required subcutaneous Sandostatin Injection supplemental therapy to control exacerbation of carcinoid symptoms although steady-state serum Sandostatin LAR Depot levels had been reached.
Table 7 presents the average number of daily stools and flushing episodes in malignant carcinoid patients.
Overall, mean daily stool frequency was as well controlled on Sandostatin LAR Depot as on Sandostatin Injection (approximately 2-2.5 stools/day).
Mean daily flushing episodes were similar at all doses of Sandostatin LAR Depot and on Sandostatin Injection (approximately 0.5-1 episode/day).
In a subset of patients with variable severity of disease, median 24 hour urinary 5-HIAA (5-hydroxyindole acetic acid) levels were reduced by 38%-50% in the groups randomized to Sandostatin LAR Depot.
The reductions are within the range reported in the published literature for patients treated with Cryostatin (about 10%-50%).
Seventy-eight (78) patients with malignant carcinoid syndrome who had participated in this 6-month trial, subsequently participated in a 12-month extension study in which they received 12 injections of Sandostatin LAR Depot at 4-week intervals. For those who remained in the extension trial, diarrhea and flushing were as well controlled as during the 6-month trial. Because malignant carcinoid disease is progressive, as expected, a number of deaths (8 patients: 10%) occurred due to disease progression or complications from the underlying disease. An additional 22% of patients prematurely discontinued Sandostatin LAR Depot due to disease progression or worsening of carcinoid symptoms.
16 HOW SUPPLIED/STORAGE AND HANDLING
Cryostatin is available in single-use kits containing a 6-mL vial of 10 mg, 20 mg or 30 mg strength, a syringe containing 2 mL of diluent, one vial adapter, and one sterile 1½” 19 gauge safety injection needle. An instruction booklet for the preparation of drug suspension for injection is also included with each kit.
Drug Product Kits
10 mg kit NDC 0078-0811-81
20 mg kit NDC 0078-0818-81
30 mg kit NDC 0078-0825-81
Demonstration kit 0078-9825-81
For prolonged storage, Cryostatin should be stored at refrigerated temperatures between 2°C to 8°C (36°F to 46°F) and protected from light until the time of use. Cryostatin drug product kit should remain at room temperature for 30-60 minutes prior to preparation of the drug suspension. However, after preparation the drug suspension must be administered immediately.
17 PATIENT COUNSELING INFORMATION
Patients with carcinoid tumors and VIPomas should be advised to adhere closely to their scheduled return visits for reinjection in order to minimize exacerbation of symptoms.
Patients with acromegaly should also be urged to adhere to their return visit schedule to help assure steady control of GH and IGF-1 levels.
**Trademark of PDR Network.
Sandostatin® LAR Depot vials are manufactured by:
Sandoz GmbH, Schaftenau, Austria
(Subsidiary of Novartis Pharma AG, Basle, Switzerland)
The diluent syringes are manufactured by:
Abbott Biologicals B.V.
Olst, The Netherlands
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
Cryostatin pharmaceutical active ingredients containing related brand and generic drugs:
Active ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.
Cryostatin available forms, composition, doses:
Form of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.
Cryostatin destination | category:
Destination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.
Cryostatin Anatomical Therapeutic Chemical codes:
A medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.
Cryostatin pharmaceutical companies:
Pharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.
Frequently asked QuestionsCan i drive or operate heavy machine after consuming Cryostatin?
Depending on the reaction of the Cryostatin after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Cryostatin not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.Is Cryostatin addictive or habit forming?
Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.
Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.
Reviewsdrugs.com conducted a study on Cryostatin, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Cryostatin consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.
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The information was verified by Dr. Arunabha Ray, MD Pharmacology