Etoposide

Class: Antineoplastic Agents
VA Class: AN900
Chemical Name: [5R - [5α,5aβ,8aα,9β(R*)]] - 9 - [4,6 - O - ethylidene - β - d - glucopyranosyl)oxy]5,8,8a,9 - tetrahydro - 5 - (4 - hydroxy - 3,5 - dimethoxyphenyl)furo[3′,4′:6,7]naphtho[2,3 - d] - 1,3 - dioxol - 6(5aH) - one
Molecular Formula: C₂₉H₃₂O₁₃
CAS Number: 33419-42-0
Brands: Etopophos, Toposar, VePesid

• Experience of Supervising Clinician


• 
  

  For administration only under the supervision of a qualified clinician experienced in the use of antineoplastic agents.^{c d}

  
  

• Myelosuppression


• 
  

  Severe myelosuppression with resulting infection or bleeding may occur. (See Myelosuppression under Cautions.)^{c d}

  
  

Introduction

Antineoplastic agent; semisynthetic podophyllotoxin-derivative.^{1 2 3}

Uses for Etoposide

Testicular Cancer

Component of various combination chemotherapeutic regimens for treatment of refractory testicular tumors in patients who have already received appropriate surgery, chemotherapy, and radiation therapy.^{1 256}

Component of various combination chemotherapeutic regimens with cisplatin for first-line treatment of stage III or unresectable stage II nonseminomatous testicular carcinoma^{39 40 41 42 206} and for chemotherapy-refractory disease.^{2 38 39 43 44 165 182}

Combination chemotherapy with etoposide, cisplatin, and bleomycin (BEP) is recommended for initial treatment of advanced nonseminomatous testicular carcinoma.^{198 206 207 208 209 210 211 212 213}

Component of a combination chemotherapeutic regimen (ifosfamide, cisplatin, and either etoposide or vinblastine) as second-line therapy for recurrent nonseminomatous testicular carcinoma.^{223 241 243 244 245 246 247}

Component of combination chemotherapeutic regimens (with cisplatin) for initial treatment of disseminated seminoma testis^{45 50 51 198 214} and treatment-refractory disease.^{38 43}

Component of combination chemotherapeutic regimens (usually with cisplatin) for initial treatment of advanced extragonadal germ-cell tumors.⁵²

Small Cell Lung Cancer

Component of a combination chemotherapeutic regimen with etoposide and cisplatin or carboplatin (PE) as a preferred first-line treatment of small-cell lung cancer.^{a 65 79 80 81 82 83 84 180 183 215 253}

In combination with ifosfamide with mesna and cisplatin (VIP) or carboplatin (ICE)^{215 249 250 252 253 254 255} as second-line therapy for the treatment of refractory small-cell lung cancer.^{65 81 82 83 183 215 249 250 252 253 254 255}

In combination with cyclophosphamide and doxorubicin (or vincristine)^{61 69 70 71 72 73 86 190 199 200 201} for treatment of extensive-stage disease.²⁵³

Non-small Cell Lung Cancer

Combination chemotherapy with etoposide and cisplatin has been used for second-line treatment of advanced non-small cell lung cancer†,^{93 94 95 96 204 205} but paclitaxel-containing ^{215 237 301 302} or other platinum-based regimens^{215 237} currently are preferred.

Hodgkin's Disease

Component of combination chemotherapeutic regimens for treatment of advanced or refractory Hodgkin's lymphoma†.^{a 14 64 100 101 110 116 118 119 121 123 129}

Non-Hodgkin's Lymphoma

Component of various combination chemotherapeutic regimens for treatment of advanced non-Hodgkin's lymphoma†.^{13 14 54 64 100 101 115 116 117 118 119 120}

Component of combination chemotherapeutic regimens (e.g., etoposide, ifosfamide, and methotrexate) for treatment of advanced diffuse lymphomas of unfavorable histology (e.g., diffuse histiocytic lymphoma)†.^{54 100 101 115 117 118 120 121 122 123 124 125 126 127}

Cutaneous T-cell Lymphoma

Has been used with transient responses in patients with cutaneous T-cell lymphoma (mycosis fungoides†).¹²⁸

Acute Myeloid Leukemia

Used alone^{54 100 101 102 103 104 105 106 107 108 109 110} and in various combination chemotherapeutic regimens^{11 107 108 111 112} for treatment of refractory acute myeloid (myelogenous, nonlymphocytic) leukemia (AML, ANLL)† in adults and children.^{14 34 54 67 100 101 102 103 104 105 106 107 108 109 110}

Particularly effective for the treatment of acute monocytic and myelomonocytic leukemias†;^{34 54 100 101 102 103 104 107 110} may be useful when monocytoid cells are not cleared with conventional combination chemotherapy.^{100 101 102 103 104 107 110}

Acute Lymphocytic Leukemia

Has been used alone and in combination chemotherapy for remission induction in refractory acute lymphocytic (lymphoblastic) leukemia (ALL)† in a limited number of children;^{108 109 110} little, if any, activity in adults.^{100 101 107}

Wilms' Tumor

Component of a combination chemotherapeutic regimen (e.g., carboplatin with etoposide) as second-line (salvage) therapy for treatment of recurrent (relapsed or refractory) Wilms' tumor†^{231 232 234 235} including recurrent tumors of unfavorable histology, abdominal recurrence after radiation therapy, or recurrence within 6 months of nephrectomy or after initial combination chemotherapy.^{231 232 239}

Alternative to standard preferred regimens in patients with less severe stages of Wilms’ tumor†.²¹⁵

Second-line high-dose therapy followed by autologous bone marrow transplantation also has been used effectively in recurrent disease.^{231 232}

Offer patients with recurrent disease (i.e., salvage therapy failure) treatment under protocol conditions in ongoing clinical trials.²³¹

Neuroblastoma

Component of combination chemotherapeutic regimens (cyclophosphamide, doxorubicin, cisplatin, and/or etoposide or teniposide) as preferred first-line therapy for neuroblastoma†.^{a 64 109 110 157 215 226 227 228 239}

Kaposi's Sarcoma

Used alone or in combination chemotherapeutic regimens^{257 258 259} as second-line therapy^{a 133 215 258} for palliative treatment of AIDS-related Kaposi's sarcoma†. ²¹⁵

Ovarian Cancer

Has been used orally as second-line therapy for advanced epithelial ovarian cancer†.^{a 215 312 313 314 315 316}

Component of a combination chemotherapeutic regimen with bleomycin and cisplatin (BEP) as first-line therapy for ovarian germ cell tumors†.^{215 317 a}

Other Uses

Component of alternating chemotherapeutic regimens (vincristine, doxorubicin and cyclophosphamide alternating with ifosfamide and mesna and etoposide) as first-line therapy for Ewing's sarcoma†.^{a 54 110 157}

Component of a chemotherapeutic regimen with methotrexate, dactinomycin, cyclophosphamide, and vincristine (EMA-CO), or with cisplatin as second-line therapy for gestational trophoblastic tumors† (choriocarcinoma†).^a Also has been used for treatment of chorioadenoma destruens†.^{130 185 a}

May be useful for treatment of hepatoma†.^{110 131 132}

May be useful as second-line therapy for treatment of rhabdomyosarcoma†.^{a 64 109 110}

Etoposide Dosage and Administration

General

• 
  

  Consult specialized references for procedures for proper handling and disposal of antineoplastics.^{b c d} (See IV Administration under Dosage and Administration.)

  
  

Administration

Administer orally¹⁸⁹ or IV.^{1 189 256}

Intraperitoneal and intrapleural administration is not recommended; delayed, severe (sometimes fatal) toxicity has occurred in animals following administration by these routes. ^{139 155}

Observe closely for possible hypotensive or anaphylactoid reactions during administration of the drug.¹ (See Hypotension and also see Sensitivity Reactions, under Cautions.)

Oral Administration

Administer etoposide capsules orally.^c

IV Administration

Administer diluted etoposide concentrate for injection by slow IV infusion.^{1 189}

Administer etoposide phosphate by IV infusion.²⁵⁶

Use syringes with Luer-Lok fittings for handling of etoposide concentrate for injection;² under pressure, needles have become displaced from etoposide-containing syringes without Luer-Lok fittings.²

Plastic devices composed of acrylic or ABS (a polymer composed of acrylonitrile, butadiene, and styrene) may crack and leak when used with undiluted etoposide injection.¹⁸⁹

Etoposide solutions containing 0.1–0.4 mg/mL in 0.9% sodium chloride or 5% dextrose injection have been filtered through several commercially available filters (e.g., 0.22-mcm Millex-GS or Millex-GV) without filter decomposition.^{2 159}

Reconstitution

Reconstitute vial containing 100 mg of etoposide phosphate powder with 5 or 10 mL sterile water for injection, 5% dextrose injection, 0.9% sodium chloride, bacteriostatic water for injection (with benzyl alcohol), or bacteriostatic sodium chloride for injection (with benzyl alcohol) to provide a solution containing 20 mg etoposide per mL (22.7 etoposide phosphate per mL) or 10 mg etoposide per mL (11.4 mg etoposide phosphate per mL), respectively.²⁵⁶

May administer reconstituted etoposide phosphate with or without further dilution.²⁵⁶

Dilution

Etoposide concentrate for injection must be diluted before administration.^{1 2 5 189}

Dilute required dose of concentrate for injection to a final concentration of 0.2 or 0.4 mg/mL in 0.9% sodium chloride or 5% dextrose injection.^{1 2}

Reconstituted etoposide phosphate solutions may be further diluted with either 5% dextrose injection or 0.9% sodium chloride injection to concentrations as low as 0.1 mg of etoposide per mL.²⁵⁶

Rate of Administration

Do not administer etoposide solutions by rapid IV injection.¹ (See Hypotension under Cautions.)

Administer etoposide IV infusions over at least 30–60 minutes to minimize the risk of hypotensive reactions.¹ If hypotensive reaction occurs, use slower rate of infusion if restarting after discontinuance and appropriate treatment.^{1 2}

A longer duration of administration may be used if the volume of fluid to be infused is a concern.¹⁸⁹

Has been administered by continuous IV infusion over 5 days,^{134 135 136} but no therapeutic advantage with this method over intermittent IV infusions.¹⁵⁶

May administer etoposide phosphate solutions over 5–210 minutes.²⁵⁶

Dosage

Available as etoposide and etoposide phosphate; dosage is expressed in terms of etoposide; 113.6 mg of etoposide phosphate is equivalent to 100 mg of etoposide.²⁹⁶

Base dosage on the clinical and hematologic response and tolerance of the patient and whether or not other chemotherapy or radiation therapy has been or is also being used in order to obtain optimum therapeutic results with minimum adverse effects.^{1 2}

Consult published protocols for the dosage, method, and sequence of administration of etoposide and other chemotherapeutic agents used in combination chemotherapeutic regimens.^b

Do not administer a repeat course until the patient’s hematologic function is within acceptable limits.¹

Toxicity profile of etoposide phosphate infused at doses exceeding 175 mg/m² has not been delineated.²⁵⁶

Adults

Testicular Cancer

Induction of Remission for Refractory Testicular Neoplasms

IV

Combination chemotherapy regimens: Usually, 50–100 mg/m² daily for 5 consecutive days every 3–4 weeks or 100 mg/m² daily on days 1, 3, and 5 every 3–4 weeks,¹ for 3 or 4 courses of therapy.^{38 43 44}

When the consecutive-day dosage regimen is employed, some clinicians administer etoposide for 3–5 days, depending on the patient’s hematologic tolerance.^{38 43}

Small Cell Lung Cancer

Oral

Twice the IV dosage rounded to the nearest 50 mg is recommended.¹⁸⁹

IV

Combination chemotherapy regimens: Usually, ranges from 35 mg/m² daily for 4 consecutive days to 50 mg/m² daily for 5 consecutive days, every 3–4 weeks.^{188 256}

Optimum duration not clearly defined; no additional improvement in survival when duration of therapy >3–6 months for limited-stage or >6 months for extensive-stage disease.²⁵³

Kaposi's Sarcoma

AIDS-Related Kaposi's Sarcoma†

IV

150 mg/m² daily for 3 consecutive days every 4 weeks; repeat cycles of therapy and reduce dosage as necessary depending on the patient’s response and the myelosuppressive effect of the drug.¹³³

Special Populations

Hepatic Impairment

Use with caution; consider the need for dosage reduction.^{159 163 176}

Renal Impairment

Cl_cr >50 mL/minute: no initial dose modification required.²⁵⁶

Cl_cr 15–50 mL/minute: administer 75% of the initial recommended dose.²⁵⁶

Cl_cr <15 mL/minute: consider further dose reduction; specific data are not available.²⁵⁶

Base subsequent doses on patient tolerance and clinical effect.²⁵⁶

Cautions for Etoposide

Contraindications

• 
  

  Known hypersensitivity to etoposide, etoposide phosphate, or any ingredient in the formulations.^{1 2 189 256}

  
  

Warnings/Precautions

Warnings

Myelosuppression

Risk of dose-limiting and potentially fatal myelosuppression,^{1 2 17 59 64 106 110 116 118 120 133 134 135 136 256} manifested commonly by leukopenia (principally granulocytopenia);^{1 2 17 57 59 64 67 91 100 101 256} thrombocytopenia ^{1 2 17 64 67 91 100 101} and anemia may also occur.^{17 60 64 133 189} Severe myelosuppression with resulting infection or bleeding may occur.^{1 2 92 100 105 118 120 133 134 135 136}

Granulocyte and platelet nadirs usually occur within 7–14 and 9–16 days, respectively, after administration of etoposide,^{1 2 59 67 106 134 136} and within 12–19 and 10–15 days, respectively, after administration of etoposide phosphate;²⁵⁶ leukocyte nadir usually occurs within 15–22 days after administration of etoposide phosphate.²⁵⁶ Bone marrow recovery is usually complete within 20 days after administration,^{1 2 56 60 67 134 135} but may occasionally require longer periods.^{17 106 136}

Monitor hematologic function frequently during and after treatment.^{1 2} Perform CBC (leukocyte count with differential, platelet count, hemoglobin) prior to initiation of therapy, at appropriate intervals during the course of treatment (e.g., twice weekly),¹⁸⁰ and before each subsequent course of treatment.^{1 2}

Suspend therapy if the platelet count is <50,000/mm³ or absolute neutrophil count is <500/mm³.^{1 2} Resume therapy when blood counts have returned to an acceptable level, if indicated.^{1 2}

If severe hematologic toxicity occurs, consider supportive therapy, antibiotics for complicating infections, and blood product transfusions.^{105 133 135 136}

Hypotension

Transient hypotension reported following rapid IV administration of etoposide.^{1 2 57 110}

Observe closely for possible hypotensive reactions.¹

Administer IV infusions slowly (i.e., over at least 30–60 minutes) to minimize the risk of hypotensive reactions.¹

Hypotension occurring during administration usually subsides with infusion discontinuance, administration of IV fluids or other supportive therapy as necessary.^{1 2}

Use slower rate of infusion if restarting after discontinuance and appropriate treatment.^{1 2}

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; teratogenicity and embryolethality demonstrated in animals.^{c d} Avoid pregnancy during therapy.^{c d} If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.^{c d}

Carcinogenicity

Acute leukemia (with or without a preleukemic phase) has been reported rarely in patients receiving etoposide in association with other antineoplastic agents.^{189 256}

Animal studies to determine the carcinogenic potential of etoposide have not been performed to date;^{1 256} however, the drug should be considered a potential carcinogen.¹

Sensitivity Reactions

Hypersensitivity Reactions

Anaphylactoid reactions consisting principally of chills,^{1 2 67 92 256} rigors,²⁵⁶ diaphoresis,^{64 256} pruritus,²⁵⁶ loss of consciousness,²⁵⁶ nausea,²⁵⁶ vomiting,²⁵⁶ fever,^{1 2} bronchospasm,^{1 2 178 256} dyspnea,^{1 2 141 178 256} tachycardia,^{1 2 256} hypertension,^{189 256} and/or hypotension^{1 2 92 178 256} reported.^{1 2 67 92 134 178 256}

Observe closely for possible anaphylactic reactions.¹

Appropriate equipment for maintenance of an adequate airway and other supportive measures and agents for the treatment of these reactions should be readily available whenever etoposide is administered.¹

Stevens-Johnson syndrome,²⁵⁶ rash,^{1 2 189 256} pigmentation,¹⁸⁹ urticaria,^{189 256} and severe pruritus^{64 189 256} occur infrequently.^{1 2 142 179}

If a hypersensitivity reaction occurs during administration, discontinue infusion and institute appropriate therapy (e.g., antihistamines, epinephrine, oxygen, corticosteroids) as necessary.¹

The role of infusion concentration or rate in the development of hypersensitivity reactions is uncertain.^{189 256}

General Precautions

Toxicity

Highly toxic drug with a low therapeutic index; therapeutic response is not likely to occur without some evidence of toxicity.^{1 2 34 139}

Administer only under constant supervision by clinicians experienced in therapy with cytotoxic agents and only when the potential benefits outweigh the possible risks.¹

Most adverse effects are reversible if detected promptly.¹

Discontinue or reduce dosage and institute appropriate measures as necessary when severe adverse effects occur.¹

Reinstitute therapy with caution, considering further need for the drug and possible toxicity recurrence.¹

Specific Populations

Pregnancy

Category D.^c (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether etoposide is distributed into milk.¹ Discontinue nursing or the drug.¹

Pediatric Use

Safety and efficacy not established.^{1 256}

Higher rates of anaphylactoid reactions reported in children receiving infusions at higher than recommended concentrations.^{189 256} (See Hypersensitivity Reactions under Cautions.)

Has been used with encouraging results for refractory acute myelogenous leukemia†,^{11 108 109 110 112} has shown some activity against refractory acute lymphocytic leukemia†^{108 110} and other pediatric malignancies†,^{109 110 157} but additional evaluation is needed.^{108 109 110 157}

Each mL of etoposide concentrate for injection contains 30 mg of benzyl alcohol.^c Although a causal relationship has not been established, injections preserved with benzyl alcohol have been associated with toxicity in neonates.^{216 217 218 219 220 221}

Concentrate for injection contains polysorbate 80A complex; potentially fatal syndrome (e.g., thrombocytopenia, ascites, and renal, pulmonary, and hepatic failure) has occurred in several premature infants who received a vitamin E product (IV) with polysorbate 80.¹⁸⁹

Hepatic Impairment

Effects of hepatic impairment on etoposide elimination have not been fully evaluated.^{20 21 28 163 176 197}

Toxicity of rapidly infused etoposide phosphate in hepatic impairment has not been adequately evaluated.²⁵⁶

Use with caution, consider the need for dosage reduction; more severe hematologic toxicity reported with elevated serum bilirubin concentrations in one study.¹⁶³ Some evidence of reduced total plasma clearance and elimination.^{28 159 163 176}

Renal Impairment

Dosage adjustments recommended based on degree of renal impairment.^{20 21 161 256} (See Renal Impairment under Dosage and Administration.)

Toxicity of rapidly infused etoposide phosphate in renal impairment has not been adequately evaluated.²⁵⁶

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether safety and efficacy for treatment of testicular tumors in geriatric patients differ from safety and efficacy in younger adults.^f

Response in patients ≥65 years of age with small cell lung cancer similar to that in younger adults.^f

Substantially eliminated by kidneys; assess renal function periodically since geriatric patients more likely to have decreased renal function.^f Dosage adjustments may be required.^f (See Renal Impairment under Dosage and Administration.)

Geriatric patients may be particularly susceptible to etoposide-induced adverse effects.¹³⁷

Common Adverse Effects

Leukopenia,^{1 2 17 57 59 64 67 91 100 101 256} thrombocytopenia,^{1 2 17 64 67 91 100 101} neutropenia,²⁵⁶ anemia,^{17 60 64 133 189} nausea,^{1 2 17 60 67 91 100 109 189 256} vomiting,^{1 2 17 60 67 91 100 109 189 256} anorexia,^{1 2 67 92 101 116 134 256} mucositis,²⁵⁶ diarrhea,^{1 2 109 134 136 256} alopecia,^{1 2 17 60 64 67 100 101 109 133 134 189 256} asthenia/malaise,^c fatigue,^{1 2} chills and/or fever.^c

Interactions for Etoposide

Specific Drugs

Drug	Interaction	Comments
Antineoplastic agents (cisplatin, carmustine, cytarabine, cyclophosphamide)	Potential additive or synergistic antineoplastic activity43 44 65 79 80 81 82 83 152 153 154
Cisplatin	Possible decreased etoposide elimination176	Limited data, further documentation needed; consider potential effect when administering etoposide to patients who received prior cisplatin therapy176
Cyclosporine (high-dose)	Possible decreased total body clearance of etoposide with concomitant use of oral etoposide and high-dose cyclosporine 256
Inhibitors of phosphatase activity (e.g., levamisole HCl)		Use caution with etoposide phosphate256

Etoposide Pharmacokinetics

Absorption

Bioavailability

Oral capsules: about 50% (range: 25–75%).^{17 18 19 160 161 189 190 191 192 193 194 195 196 197}

Distribution

Extent

Not fully characterized.^{18 21 24 27 28} Following IV administration, distributed minimally into pleural fluid^{21 27} and has been detected in the saliva,¹⁹⁷ liver,¹⁷³ spleen,¹⁷³ kidney,¹⁷³ myometrium,^{189 197} healthy brain tissue,²⁷ and brain tumor tissue.^{27 175}

Does not readily penetrate the CNS;^{1 18 21 22 27 29 30 197} variable CSF concentrations generally ranging from undetectable^{18 22} to <5% of concurrent plasma concentrations^{21 29 30 162}

Apparently crosses the placenta in animals,^{1 2} not known whether distributed into milk.¹

Plasma Protein Binding

Approximately 97% at 10 mcg/mL in vitro.^{c f}

Elimination

Metabolism

Metabolized principally to inactive hydroxy acid^{21 25 26 30 32 33 177} (probably the trans-hydroxy acid).³³

Elimination Route

Following IV infusion, excreted principally (40–60%) in urine as unchanged drug (20–30% within 24 hours,^{18 29 30} 30–45% within 48 hours)^{20 161} and metabolites in 48–72 hours.^{18 20 21 26 27 29 30 32} 2–16% is excreted in feces within 72 hours;^{29 30} .^{28 173 174 197}

Following oral administration, about 5–25% of the dose is excreted in urine within 24–48 hours.^{191 194 195 196 197}

Half-life

Biphasic,^{18 21 22 24 25 27 29 30}

Polyotic

In some countries, this medicine may only be approved for veterinary use.

Ingredient matches for Polyotic

Tetracycline

Tetracycline hydrochloride (a derivative of Tetracycline) is reported as an ingredient of Polyotic in the following countries:

• United States

International Drug Name Search

Sandostatin LAR

Generic Name: octreotide acetate

Dosage Form: injection
FULL PRESCRIBING INFORMATION

Indications and Usage for Sandostatin LAR

Sandostatin LAR Depot 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.

Acromegaly

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 [see Clinical Studies (14) and Dosage and Administration (2)].

Carcinoid Tumors

Long-term treatment of the severe diarrhea and flushing episodes associated with metastatic carcinoid tumors.

Vasoactive Intestinal Peptide Tumors (VIPomas)

Long-term treatment of the profuse watery diarrhea associated with VIP-secreting tumors.

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.

 DOSAGE AND ADMINISTRATION

• Sandostatin LAR Depot should be administered by a trained health care provider. It is important to closely follow the mixing instructions included in the packaging. Sandostatin LAR Depot must be administered immediately after mixing.
  


• Do not directly inject diluent without preparing suspension.
  


• The recommended needle size for administration of Sandostatin LAR Depot is the 1½” 19 gauge needle (supplied in the drug product kit). For patients with a greater skin to muscle depth, a 2” 19 gauge needle (not supplied) may be used.
  


• Sandostatin LAR Depot should be administered intramuscularly in the gluteal region at 4-week intervals. Administration of Sandostatin LAR Depot at intervals greater than 4 weeks is not recommended.
  


• Injection sites should be rotated in a systematic manner to avoid irritation. Deltoid injections should be avoided due to significant discomfort at the injection site when given in that area.
  


• Sandostatin LAR Depot should never be administered intravenously or subcutaneously.

The following dosage regimens are recommended.

Acromegaly

Patients Not Currently Receiving Octreotide Acetate

Patients not currently receiving octreotide 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 octreotide. 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:

• GH ≤2.5 ng/mL, IGF-1 normal and clinical symptoms controlled: maintain Sandostatin LAR Depot dosage at 20 mg every 4 weeks.
  


• GH >2.5 ng/mL, IGF-1 elevated, and/or clinical symptoms uncontrolled, increase Sandostatin LAR Depot dosage to 30 mg every 4 weeks.
  


• GH ≤1 ng/mL, IGF-1 normal and clinical symptoms controlled, reduce Sandostatin LAR Depot dosage to 10 mg every 4 weeks.
  


• If GH, IGF-1, or symptoms are not adequately controlled at a dose of 30 mg, the dose may be increased to 40 mg every 4 weeks. Doses higher than 40 mg are not recommended.

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.

Carcinoid Tumors and VIPomas

Patients Not Currently Receiving Octreotide Acetate

Patients not currently receiving octreotide 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 (mean daily dosage is 300 mcg). 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 octreotide 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 octreotide 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:

• If symptoms are adequately controlled, consider a dose reduction to 10 mg for a trial period. If symptoms recur, dosage should then be increased to 20 mg every 4 weeks. Many patients can, however, be satisfactorily maintained at a 10-mg dosage every 4 weeks.
  


• If symptoms are not adequately controlled, increase Sandostatin LAR Depot to 30 mg every 4 weeks if symptoms are not adequately controlled. Patients who achieve good control on a 20-mg dose may have their dose lowered to 10 mg for a trial period. If symptoms recur, dosage should then be increased to 20 mg every 4 weeks.
  


• Dosages higher than 30 mg are not recommended.

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.

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)].

Special Populations: Hepatic Impairment – Cirrhotic Patients

In patients with established cirrhosis of the liver, the starting dose should be 10 mg every 4 weeks [see Clinical Pharmacology (12)].

 DOSAGE FORMS AND STRENGTHS

Sandostatin LAR Depot is available in single-use kits containing a 5-mL vial of 10 mg, 20 mg, or 30 mg strength, a syringe containing 2.5 mL of diluent, two sterile 1½” 19 gauge needles, and two alcohol wipes. An instruction booklet for the preparation of drug suspension for injection is also included with each kit.

 CONTRAINDICATIONS

None

 WARNINGS AND PRECAUTIONS

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 [see Adverse Reactions (6)].

Hyperglycemia and Hypoglycemia

Octreotide 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 [see Adverse Reactions (6)].

Thyroid Function Abnormalities

Octreotide suppresses the secretion of thyroid-stimulating hormone, which may result in hypothyroidism. Baseline and periodic assessment of thyroid function (TSH, total and/or free T4) is recommended during chronic octreotide therapy [see Adverse Reactions (6)].

Cardiac Function Abnormalities

In both acromegalic and carcinoid syndrome patients, bradycardia, arrhythmias and conduction abnormalities have been reported during octreotide therapy. Other EKG 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 octreotide acetate is not established because many of these patients have underlying cardiac disease. Dose adjustments in drugs such as beta-blockers that have bradycardia 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 [see Adverse Reactions (6)].

Nutrition

Octreotide may alter absorption of dietary fats.

Depressed vitamin B12 levels and abnormal Schilling tests have been observed in some patients receiving octreotide therapy, and monitoring of vitamin B12 levels is recommended during therapy with Sandostatin LAR Depot.

Octreotide has been investigated for the reduction of excessive fluid loss from the G.I. 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 octreotide should have periodic monitoring of zinc levels.

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 [see Dosage and Administration (2.0)].

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

Drug Interactions

Octreotide has been associated with alterations in nutrient absorption, so it may have an effect on absorption of orally administered drugs. Concomitant administration of octreotide injection with cyclosporine may decrease blood levels of cyclosporine [see Drug Interactions (7.2)].

 ADVERSE REACTIONS

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.

Acromegaly

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.

Table 1. Adverse Events Occurring in ≥10% of Acromegalic Patients in the Phase 3 Studies

WHO Preferred Term	Phase 3 Studies (Pooled) Number (%) of Subjects with AE’s 10 mg/20 mg/30 mg (n=261) n (%)
Diarrhea	93 (35.6)
Abdominal Pain	75 (28.7)
Flatulence	66 (25.3)
Influenza-Like Symptoms	52 (19.9)
Constipation	46 (17.6)
Headache	40 (15.3)
Anemia	40 (15.3)
Injection Site Pain	36 (13.8)
Cholelithiasis	35 (13.4)
Hypertension	33 (12.6)
Dizziness	30 (11.5)
Fatigue	29 (11.1)

The safety of Sandostatin LAR in the treatment of acromegaly was also evaluated in a postmarketing randomized phase 4 study. 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 and 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.

Table 2. Adverse Events Occurring in ≥10% of Acromegalic Patients in Phase 4 Study

WHO Preferred Term	Phase 4 Study SAS LAR N=76 n (%)	Phase 4 Study Surgery N=64 n (%)
Diarrhea	36 (47.4)	2 (3.1)
Cholelithiasis	29 (38.2)	3 (4.7)
Abdominal Pain	19 (25.0)	2 (3.1)
Nausea	12 (15.8)	5 (7.8)
Alopecia	10 (13.2)	5 (7.8)
Injection Site Pain	9 (11.8)	0
Abdominal Pain Upper	8 (10.5)	0
Headache	8 (10.5)	6 (9.4)
Epistaxis	0	7 (10.9)

Gallbladder Abnormalities

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 octreotide, 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 octreotide 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 octreotide, 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 [see Warnings and Precautions (5)].

Hypothyroidism

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 acromegalics treated with Sandostatin LAR Depot, hypothyroidism was reported as an adverse event in 2% and goiter in 2%. Two patients receiving Sandostatin LAR Depot required initiation of thyroid hormone replacement therapy [see Warnings and Precautions (5)].

Cardiac

In acromegalics, 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 octreotide acetate is not established because many of these patients have underlying cardiac disease [see Warnings and Precautions (5)].

Gastrointestinal

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.

Table 3. Number (%) of Acromegalic Patients with Common G.I. Adverse Events

Adverse Event	Sandostatin Injection S.C. Three Times Daily n=114		Sandostatin LAR Depot Every 28 Days n=261
	n	%	n	%
Diarrhea	66	(57.9)	95	(36.4)
Abdominal Pain or Discomfort	50	(43.9)	76	(29.1)
Nausea	34	(29.8)	27	(10.3)
Flatulence	15	(13.2)	67	(25.7)
Constipation	10	(8.8)	49	(18.8)
Vomiting	5	(4.4)	17	(6.5)

Only 2.6% of the patients on Sandostatin Injection in U.S. clinical trials discontinued therapy due to these symptoms. No acromegalic patient receiving Sandostatin LAR Depot discontinued therapy for a G.I. 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 acromegalics receiving doses of 10 mg, 20 mg, and 30 mg, respectively, of Sandostatin LAR Depot. 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 Octreotide

Studies to date have shown that antibodies to octreotide develop in up to 25% of patients treated with octreotide acetate. These antibodies do not influence the degree of efficacy response to octreotide; 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 octreotide 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.

Table 4. Adverse Events Occurring in ≥15% of Carcinoid Tumor and VIPoma Patients in Study 1

	Number (%) of Subjects with AE’s (n=93)
WHO Preferred Term	Sc N=26	10 mg N=22	20 mg N=20	30 mg N=25
Abdominal Pain	8 (30.8)	8 (35.4)	2 (10.0)	5 (20.0)
Arthropathy	5 (19.2)	2 (9.1)	3 (15.0)	2 (8.0)
Back Pain	7 (26.9)	6 (27.3)	2 (10.0)	2 (8.0)
Dizziness	4 (15.4)	4 (18.2)	4 (20.0)	5 (20.0)
Fatigue	3 (11.5)	7 (31.8)	2 (10.0)	2 (8.0)
Flatulence	3 (11.5)	2 (9.1)	2 (10.0)	4 (16.0)
Generalized Pain	4 (15.4)	2 (9.1)	3 (15.0)	1 (4.0)
Headache	5 (19.2)	4 (18.2)	6 (30.0)	4(16.0)
Musculoskeletal Pain	4 (15.4)	0	1 (5.0)	0
Myalgia	0	4 (18.2)	1 (5.0)	1 (4.0)
Nausea	8 (30.8)	9 (40.9)	6 (30.0)	6 (24.0)
Pruritus	0	4 (18.2)	0	0
Rash	1 (3.8)	0	3 (15.0)	0
Sinusitis	4 (15.4)	0	1 (5.0)	3 (12.0)
URTI	6 (23.1)	4 (18.2)	2 (10.0)	3 (12.0)
Vomiting	3 (11.5)	0	0	4 (16.0)

Gallbladder Abnormalities

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 [see Warnings and Precautions (5)].

Hypothyroidism

In carcinoid patients, hypothyroidism has only been reported in isolated patients and goiter has not been reported [see Warnings and Precautions (5)].

Cardiac

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 octreotide acetate is not established because many of these patients have underlying cardiac disease [see Warnings and Precautions (5)].

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.

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.

 DRUG INTERACTIONS

Cyclosporine

Concomitant administration of octreotide injection with cyclosporine may decrease blood levels of cyclosporine and result in transplant rejection.

Insulin and Oral Hypoglycemic Drugs

Octreotide 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.

Bromocriptine

Concomitant administration of octreotide and bromocriptine increases the availability of bromocriptine.

Other Concomitant Drug Therapy

Concomitant administration of bradycardia-inducing drugs (e.g., beta-blockers) may have an additive effect on the reduction of heart rate associated with octreotide. Dose adjustments of concomitant medication may be necessary.

Octreotide has been associated with alterations in nutrient absorption, so it may have an effect on absorption of orally administered drugs.

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 octreotide 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.

 USE IN SPECIFIC POPULATIONS

Pregnancy

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 octreotide. 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 (13.2)].

Nursing Mothers

It is not known whether octreotide 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.

Pediatric Use

Safety and efficacy of Sandostatin LAR Depot in the pediatric population have not been demonstrated.

No formal controlled clinical trials have been performed to evaluate the safety and effectiveness of Sandostatin LAR Depot in pediatric patients under 6 years of age. In post-marketing 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 octreotide has not been established as the majority of these pediatric patients had serious underlying co-morbid conditions.

The efficacy and safety of Sandostatin LAR Depot was examined in a single randomized, double-blind, placebo-controlled, six-month pharmacokinetics study in 60 pediatric patients age 6-17 years with hypothalamic obesity resulting from cranial insult. The mean octreotide concentration after 6 doses of 40 mg Sandostatin LAR Depot administered by IM injection every four weeks was approximately 3 ng/mL. Steady-state concentrations was 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 (37%) patients treated with Sandostatin LAR Depot. No unexpected adverse events were observed. However, with Sandostatin LAR Depot 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 Sandostatin LAR Depot was 10 to 30 mg once a month.

Geriatric Use

Clinical studies of Sandostatin did not include sufficient numbers of subjects age 65 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.

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 (12)].

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)].

 OVERDOSAGE

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 octreotide.

 DESCRIPTION

Octreotide is the acetate salt of a cyclic octapeptide. It is a long-acting octapeptide with pharmacologic properties mimicking those of the natural hormone somatostatin. Octreotide 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*)].

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 octreotide 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 5-mL vials in 3 strengths delivering 10 mg, 20 mg, or 30 mg octreotide-free peptide. Each vial of Sandostatin LAR Depot delivers:

Name of Ingredient	10 mg	20 mg	30 mg
octreotide acetate	11.2 mg*	22.4 mg*	33.6 mg*
D, L-lactic and glycolic acids copolymer	188.8 mg	377.6 mg	566.4 mg
mannitol	41.0 mg	81.9 mg	122.9 mg

*Equivalent to 10/20/30 mg octreotide base.

Each syringe of diluent contains:
carboxymethylcellulose sodium	12.5 mg
mannitol	15.0 mg
water for injection	2.5 mL

The molecular weight of octreotide is 1019.3 (free peptide, C49H66N10O10S2) and its amino acid sequence is

 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 octreotide. 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 octreotide 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 (intragluteally) once every 4 weeks.

Mechanism of Action

Octreotide 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, octreotide has been used to treat the symptoms associated with metastatic carcinoid tumors (flushing and diarrhea), and Vasoactive Intestinal Peptide (VIP) secreting adenomas (watery diarrhea).

Pharmacodynamics

Octreotide substantially reduces and in many cases can normalize growth hormone and/or IGF-1 (somatomedin C) 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 [see Warnings and Precautions (5)].

Octreotide may cause clinically significant suppression of thyroid-stimulating hormone (TSH).

Pharmacokinetics

Sandostatin Injection

According to data obtained with the immediate-release formulation, Sandostatin Injection solution, after subcutaneous injection, octreotide 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 values were dose proportional both after subcutaneous or intravenous single doses up to 400 mcg and with multiple doses of 200 mcg three 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 octreotide 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 octreotide 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 octreotide 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 volume of distribution (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 octreotide 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, octreotide 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 octreotide 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, octreotide 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 octreotide 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, octreotide 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 octreotide 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 octreotide 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 octreotide 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 octreotide 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 d