DESCRIPTION

IntraDoseÒ (cisplatin/epinephrine) Injectable Gel is a viscous, opaque, pale yellow gel containing the antineoplastic agent, cisplatin, and the vasoconstrictor, epinephrine, in an aqueous matrix of purified bovine collagen. It is intended only for intratumoral administration. The drug product is provided as a single-use kit containing one single-use vial of IntraPlatinÔ (cisplatin for injectable suspension), one single-use vial of IntraEpiÔ (epinephrine solution, 0.152 mg/mL), and one single-use syringe of IntraGelÔ (6.5% collagen gel). The product is prepared shortly before use. Each kit will provide 2 mL of IntraDose after mixing.

When prepared as directed, 1 mL of IntraDose contains: cisplatin (4 mg), epinephrine (0.1 mg), mannitol (40 mg), sodium chloride (37 mg), purified bovine collagen (20 mg), sodium phosphate dibasic (2.1 mg), sodium phosphate monobasic (1.8 mg), polysorbate 80 (0.7 mg), acetic acid (0.3 mg), sodium metabisulfite (0.1 mg), sodium acetate (0.1 mg) and edetate disodium (0.07 mg). The pH of the mixed gel is approximately 6.2.

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IntraEpi is a sterile aqueous solution containing epinephrine (0.152 mg/mL), polysorbate 80 (1 mg/mL), glacial acetic acid (0.49 mg/mL), sodium metabisulfite (0.2 mg/mL), sodium acetate (0.15 mg/mL), and edetate disodium dihydrate (0.1 mg/mL). Hydrochloric acid and/or sodium hydroxide may be added during manufacture to adjust pH. IntraEpi differs significantly from other commercial preparations of epinephrine and is specifically designed for IntraDose preparation.

IntraGel is a sterile aqueous collagen gel formulation containing purified bovine collagen (65 mg/g); dibasic sodium phosphate, heptahydrate (17.9 mg/g); monobasic sodium phosphate, monohydrate (4.6 mg/g); and sodium chloride (2.6 mg/g).

Epinephrine is (R)-4-[1-hydroxy-2-(methylamino)ethyl]-1,2-benzenediol, C9H13NO3 (molecular weight of 183.21). Epinephrine as the free base is very slightly soluble in water and in alcohol. Epinephrine is freely soluble in water at neutral or acid pH. It has the following structure:

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In a pharmacokinetic study of IntraDose administered intratumorally to sixteen subjects (total of 20 treatments) with squamous cell carcinoma of the head and neck, platinum levels were monitored in plasma (total Pt), and plasma ultrafiltrate (free Pt). Patients received 0.25 mL gel/cm³ of tumor volume, corresponding to cisplatin doses of 10.5 to 25.6 mg, averaging approximately 10 mg/m² body surface area. The maximum average total Pt concentration in the plasma (t_max) was observed at 9.8 hours. Over this dose range, average observed total Pt peak plasma concentration (C_max) was 252 ng/mL and decreased slowly over time with a t_1/2 of 12.5 days. There was little increase or accumulation in total Pt after multiple weekly treatments. The appearance of free Pt in plasma was delayed from the time of administration with an average t_max of 45 min. The C_max was variable, ranging from 15 to 229 ng/mL with an average of 95 ng/mL that fell below the detection limits (5 ng/mL) after 4 hours. The peak free Pt levels in plasma were transient and much lower than the sustained exposure of 1.5 to 2.0 µg/mL normally considered the lower threshold for nephrotoxicity. The estimated AUC (t₀ to t¥ ) for free Pt ranged from 0.2 to 4.3 m g· h/mL. Systemic clearance of free Pt was 573 ± 155 mL/h/kg and the apparent volume of distribution during the elimination phase (V_z) was 200 L for free Pt. These observations are consistent with local sequestration of Pt at the injection site and delayed release into the systemic circulation.

Study 516-99-PK

Study TB-1616
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Study 414-93-2

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One study enrolled and treated 86 patients in North America (62 IntraDose, 24 placebo); the second study enrolled and treated 92 patients in Europe (57 IntraDose, 35 placebo). Most patients (99%) were previously treated for their head and neck cancer; most (89%) had been heavily pretreated with multiple prior treatment modalities including surgery, radiotherapy and/or chemotherapy. Most tumors were located in the cervical, oral, facial or laryngopharyngeal regions. The treatment regimen consisted of up to 6 weekly injections of IntraDose or placebo (collagen gel only) within 8 weeks to one or more tumors. The dose administered in these studies was 0.25-0.5 mL/cm³.

ISE Section 3.1.2.1

North America Europe

IntraDose Placebo IntraDose Placebo
(n= 62) (n= 24) (n=57) (n= 35)

No. (%) of responses

Complete response (CR) 14 (23%) 0 (0%) 9 (16%) 1 (3%)

Partial response (PR) 7 (11%) 0 (0%) 5 (9%) 0 (0%)
Overall response 21 (34%) 0 (0%) 14 (25%) 1 (3%)
(CR + PR)

95% Confidence Interval (22-47%) (0-14%) (14-38%) (0.072-15%)

p value 0.001 0.007

____________________________

Complete response (100% decrease in tumor volume sustained for at least 28 days)

Partial response (>50% < 100% decrease in tumor volume sustained for at least 28 days)

Study 414-94-2

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Other Solid Tumors
Two open-label studies were conducted in 126 patients with solid tumors that were metastatic or recurrent from various primary sites. Cancers included breast cancer,

melanoma and esophageal cancer as well as a wide variety of other symptomatic cancers. Most of these patients (91%) had received previous treatment and the majority (73%) had received multiple prior therapies. Patients received weekly injections of 0.5 mL of IntraDose per cm³ of tumor for up to 6 weeks. Objective tumor response and clinical benefit were evaluated for the target tumor as described above for the placebo-controlled head and neck cancer studies. In patients with breast adenocarcinoma (n = 28), the response of the target tumor was 50% with a median duration of 82 days (29-211 days). Clinical benefit was attained in 39% of patients and there was a significant association with tumor response (p = 0.033). For patients with malignant melanoma (n = 27), the response rate was 33% with a median duration of 72.5 days (30-632 days). For esophageal cancer patients (n = 24), the response rate was 29% with a median duration of 84 days (29-120 days).

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The overall objective response rate (CR and PR) for the primary target tumor in the combined studies was 35%. The overall clinical benefit rate was 31%. Of those patients who had a response, 52% attained a clinical benefit. The association between clinical benefit and response of the target tumor was statistically significant (p=0.0001).

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Patients with known hypersensitivity to any of the components in IntraDose, including cisplatin, bovine collagen, epinephrine or sulfites, should not be treated.

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Caution: IntraDose should only be administered by direct intratumoral injection. IntraDose MUST NOT be injected intravenously, intra-arterially, or intrathecally. Injection into or adjacent to a major blood vessel may cause bleeding, arterial vasospasm or vascular occlusion. In situations where there are complex anatomical relationships, use of imaging procedures to guide the injection of the drug may be advisable. Injection of IntraDose may involve a risk of damage to adjacent peripheral or cranial nerves (see PRECAUTIONS).

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Local Reactions: Injection of IntraDose into tumors results in a high intratumoral concentration of cisplatin for an extended period of time. Expected local cytotoxic effects in the tumor and adjacent tissue may include erythema, swelling, erosion, ulceration, necrosis, eschar formation and/or bleeding. The incidence of local cytotoxic effects generally peaks 2 weeks after the start of treatment and resolves over the next 3-12 weeks. In clinical studies, many patients had these tissue conditions at baseline, although most of these were mild to moderate in severity. Following treatment with IntraDose, the overall incidence and severity of local cytotoxic reactions increased in the IntraDose group. However, most of these effects were mild to moderate and resolved with standard wound care measures.

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Patients at risk for delayed wound healing due to prior surgery, radiation, poor nutrition or inadequate blood supply may be at higher risk for developing more severe local cytotoxic effects. In cases where administration of the next scheduled IntraDose treatment might be expected to intensify the severity of existing local cytotoxic effects, especially ulceration and necrosis, treatment with IntraDose should be delayed until there is adequate healing of the tumor or surrounding tissue (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).

Allergic Reactions: Anaphylactic-like reactions to platinum-containing products have been reported to occur within minutes of systemic administration in patients with prior exposure to similar compounds. The safety of IntraDose in patients with a history of anaphylaxis or a history of multiple severe allergies has not been demonstrated. Patients with a history of dietary beef allergy should be carefully evaluated before injection with products containing bovine collagen because such patients may be predisposed to allergic reaction to any bovine-derived product.

Platinol Package Insert

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ISS Section 18

IntraDose contains sodium metabisulfite, a sulfite that may cause allergic-type reactions, including anaphylactic symptoms and severe or even life-threatening asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and is probably low. Sulfite sensitivity is more frequent in asthmatic than in nonasthmatic people.

Pregnancy: IntraDose should not be used in patients who are pregnant, lactating or breast feeding. Cisplatin can cause fetal harm when administered to a pregnant woman. Cisplatin has been shown to be mutagenic in bacteria and produces chromosome aberrations in animal cells in tissue culture. Patients should be advised to avoid becoming pregnant during IntraDose therapy. If IntraDose is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Platinol Package Insert

General: Not for intravenous injection. IntraDose should only be administered by direct intratumoral injection and MUST NOT be injected intravenously, intra-arterially or intrathecally (see WARNINGS).

Physicians administering this product should be familiar with the local and surgical anatomy of the site of injection. Imaging studies such as computed tomography (CT) or magnetic resonance imaging (MRI) may be required prior to treatment with IntraDose in order to adequately define the local anatomy and to plan the approach and extent of the local injection. In some patients, imaging guidance with ultrasound or CT may assist needle placement at the site of injection.

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Local injection of IntraDose involves a risk of serious adverse experiences such as hemorrhage or cerebral vascular events, especially with tumors involving major vessels of the extracranial vascular system. Tissue damage, needle trauma to the artery, chemical irritation, mechanical pressure from a large injected volume, local inflammation and swelling or tumor progression alone or in combination with IntraDose may contribute to the occurrence of cerebral vascular events.

ISS Section 18

Pain Management: A comprehensive pain management program should be planned for each patient prior to treatment. The physician should assess the patient’s pain prior to injection and anticipate the possibility that pain will be increased during and following the injection of IntraDose. Sufficient time should be allowed for any anesthetic or analgesia to take effect prior to administration of IntraDose. It may be valuable to obtain consultation from an anesthesiologist or other pain-management specialist. Topical and other local anesthetics, loco-regional nerve blocks and systemic analgesics may be used alone or in combination, as appropriate. If a local anesthetic is used, it should be injected around the tumor margins. Local anesthetics containing epinephrine are contraindicated.

It should be assumed that narcotic-strength analgesia will be required at least for the first IntraDose administration procedure. Narcotic-strength analgesia with parenteral morphine sulfate, meperidine or fentanyl has been used in clinical trials of IntraDose, frequently in combination with lorazepam. An alternative regimen may involve local anesthesia with lidocaine and administration of midazolam hydrochloride. Provisions should be made to continue adequate analgesia for 24-48 hours following the procedure, during which time treatment with narcotic strength analgesics may be required. Subsequently, nonsteriodal anti-inflammatory drugs or acetaminophen may be adequate for pain management.

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Wound Care: Local infection may occur, particularly in previously irradiated areas or in areas with pre-existing ulceration and necrosis, where facultative anaerobes and other pathogens may thrive. Cellulitis was reported infrequently in clinical studies. Management of local infection during IntraDose therapy, with local wound care or systemic antibiotics, may be necessary. The local cytotoxic effects of IntraDose on treated tumors may include erythema, swelling, erosion, ulceration, necrosis, eschar and/or bleeding (see WARNINGS). Patients at risk for delayed wound healing due to prior surgery, radiation, poor nutrition or inadequate blood supply may be at higher risk for developing more severe local cytotoxic effects.

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Renal Effects and Dehydration: The low systemic exposure to cisplatin released from IntraDose is not expected to produce direct renal toxicity. Nevertheless, patients with advanced head and neck cancer frequently have poor oral intake and may be both dehydrated and poorly nourished. This may be especially true for elderly patients, who are also more likely to have decreased renal function. Oral intake may be further compromised in the days following IntraDose treatment due to the local cytotoxic effects of the drug or from anorexia associated with concurrent narcotic analgesics. In these patients, the need for adequate hydration and/or intravenous fluid replacement should be considered.

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Information for Patients: Patients should be informed of the expected effects of IntraDose, in particular, the likelihood of increased pain during and after injection. Patients should also be made aware that treatment may result in local skin reactions, such as erythema, swelling, erosion, ulceration, necrosis, eschar formation and/or bleeding or a worsening of these conditions that may be present before treatment with IntraDose. These effects occur within days of treatment and may become worse as treatments proceed before improvement is noted.

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Drug Interactions: No formal drug interaction studies have been conducted. In addition, the short and long-term toxicity profiles of IntraDose, when given concurrently with radiation or systemic chemotherapy, have not been studied.

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Carcinogenesis, Mutagenesis, Impairment of Fertility: The carcinogenic potential of IntraDose has not been studied. Cisplatin has been shown to be mutagenic in bacteria and produce chromosome aberrations in animal cells in tissue culture. In mice cisplatin is teratogenic and embryotoxic (see WARNINGS).

Pregnancy: Category D. Safe use during human pregnancy has not been established
(see WARNINGS) .

Platinol Package Insert

Nursing Mothers: The safety of IntraDose use in nursing mothers has not been established. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from IntraDose, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use: The safety and effectiveness of IntraDose in pediatric patients has not been established.

Geriatric Use: Of the total number of subjects in clinical studies of IntraDose, 37% percent were 65 and over, while 15% percent were 75 and over. No overall differences in safety or effectiveness were observed between these and younger subjects.

The most frequent treatment-related adverse events in the North American and European placebo-controlled studies were either immediate injection effects (pain, tachycardia or hypertension) or local reactions at the treatment site (pain, facial edema, hemorrhage, infection, neck pain or pruritis). Overall, pain was the most frequent adverse event. Some patients randomized to IntraDose or placebo experienced transient elevation of blood pressure and pulse rate during the administration of the treatment. In a few cases, these were judged to be clinically significant hypertension or tachycardia, possibly due to the injected epinephrine or the result of anxiety that accompanied injection.

The most clinically important adverse reactions observed in clinical studies with IntraDose were cerebrovascular events, cardiovascular events and significant tissue damage caused by the local cytotoxic effects of IntraDose.

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The low systemic absorption of cisplatin after intratumoral injection of IntraDose formulation is evident in the small number of adverse events that are typically attributed to systemically administered cisplatin. The most frequently reported systemic events were nausea and vomiting, asthenia and headache. These adverse events were generally mild to moderate in severity and effectively managed with supportive measures. Treatment discontinuation or delay was usually not necessary.

Placebo
IntraDose (collagen gel only)
n = 150 n = 75

Pain 40% (60) 25% (19)

Within 15 min. of injection 25% (37) 19% (14)
Localized at treatment site 25% (37) 12% (9)

Face Edema 11% (17) 1% (1)

Hemorrhage 9% (13) 5% (4)

Infection 9% (13) 3% (2)

Nausea 8% (12) 3% (2)

Hypertension 8% (12) 5% (4)

Neck Pain 8% (12) 1% (1)

Vomiting 7% (10) 1% (1)
Headache 7% (10) 1% (1)

Pruritus 6% (9) 3% (2)

Tachycardia 6% (9) 3% (2)
Asthenia 5% (7) 1% (1)

Selected treatment-related adverse reactions that occurred in 2-4% of patients in the two placebo-controlled studies are presented below in descending order of frequency. Included are clinically significant adverse reactions that occurred in 1% or less of patients regardless of relationship to treatment.

Body as a whole: Fever, cellulitis, chest pain, fistula, allergic reaction

Cardiovascular: Vasodilatation, palpitation, hypotension, vasospasm, cerebrovascular accident, arteriospasm, cerebral ischemia, cerebral infarct, heart arrest

Digestive: Anorexia, dysphagia, diarrhea, tongue edema

Hemic and Lymphatic: Anemia, leukocytosis

Metabolic and Nutritional: Edema, weight loss, hypomagnesemia, dehydration, hypercalcemia

Musculoskeletal: Joint disorder

Nervous: Dizziness, paresthesia, tremor, neuropathy, paralysis, facial paralysis, convulsion, hemiplegia

Respiratory: Dyspnea

Skin and appendages: Drainage, drainage serosanguinal, sweating

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Clinically important adverse events observed in patients treated in five IntraDose clinical studies (n=396) are described below:

Cerebrovascular Events: During the early portion of the North American placebo-controlled study, a total of six patients experienced a cerebrovascular event (5 IntraDose, 1 placebo). All of the events occurred during or shortly (within 1 to 2 hr) after treatment. These events were judged to be treatment related and most likely caused by carotid artery vasospasm. No events occurred after patients with tumors invading or threatening to invade the carotid artery were excluded from the study. The respective etiologies of these events have not been defined with certainty, and head and neck cancer itself, a known predisposing factor in cerebrovascular events, is listed among other possible causes that cannot be ruled out. Extreme care must be exercised when injecting IntraDose, particularly in areas where there are complex anatomical relationships (see CONTRAINDICATIONS and PRECAUTIONS).

ISS Section 18

Cardiovascular Events: Cardiovascular-related events, including tachycardia
(15), hypertension (23), palpitations (4) were reported in 58 (15%) IntraDose or placebo treated patients in five clinical studies. Of these events, only 12 (3%) were considered severe. One patient experienced a non-fatal cardiopulmonary arrest following injection with IntraDose. The etiology of this event has not been determined; however, the patient had a history of hypertension and peripheral vascular arteriosclerotic disease and a prior cardiac arrest of unknown etiology.

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Significant Tissue Damage: Local cytotoxic effects may result in erosion, ulceration, bleeding or fistula formation. Spontaneous hemorrhage occurred in 22 (6%) of patients. Most of these events were mild or moderate in severity. In 3 cases, the hemorrhage was severe and led to death of the patient. The possible etiologies of these events include necrosis of a tumor that involves a blood vessel (e.g. carotid artery) and tumor necrosis secondary to local cytotoxic effects of cisplatin. Caution is advised in treating tumors that are friable or bleeding. Breakdown of tumor tissue and disease progression affecting adjacent tissue can lead to superficial bleeding and fistula development. Fistulae were reported in 10 (3%) patients (9 IntraDose, 1 placebo).

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Allergic Reactions: Four patients treated with IntraDose had an allergic reaction. One patient had an anaphylactoid reaction following IntraDose treatment. A second patient had an anaphylactoid reaction to systemically administered cisplatin after completing local treatment with IntraDose and may have developed sensitivity to cisplatin following local treatment. Two other patients had immediate local allergic-like reactions limited to the site of injection. Because the causes of these allergic reactions are not known, the risk of allergic reaction to any component of IntraDose must be considered (See CONTRAINDICATIONS and WARNINGS).

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Drug Abuse and Overdosage

A 10-mL dose of IntraDose contains 1 mg epinephrine. Patients with cardiovascular disease may be at increased risk of adverse events attributable to epinephrine. Patients with pre-existing hypertension should have their blood pressure adequately controlled. Epinephrine overdosage may result in extremely elevated arterial pressure, increased risk of cerebrovascular accident, pulmonary edema, transient bradycardia followed by tachycardia, and potentially fatal cardiac arrhythmias, or ventricular premature contractions. Other reported effects may include extreme pallor and coldness of the skin, metabolic acidosis and kidney failure. Patients treated for epinephrine overdose should receive appropriate supportive care.

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Radiological imaging studies with CT, MRI, ultrasound or other specialized radiological techniques may be required to accurately identify the extent of local tumor involvement and to plan the treatment program for local tumor injection (see PRECAUTIONS).

Treat each tumor with 0.25 mL IntraDose per cm³ of tumor volume to a maximum of 10 mL of IntraDose administered at any one visit. One or more tumors may be treated on any one treatment day. IntraDose should be administered on a weekly basis for up to 6 treatments (one cycle). Estimate tumor volume by physical examination or imaging studies using the three tumor dimensions (length x width x height x 0.5). At each treatment visit, the tumor volume should be remeasured and the dose volume recalculated, as needed. Additional treatment cycles can be administered if the tumor progresses or as new tumors develop.

Tumors treated with IntraDose should be monitored on a weekly basis to assess the effect of treatment on tumor regression, as well as any local cytotoxic effects on the tumor and adjacent tissues (see WARNINGS). If needed, treatment should be delayed for one week or until there is adequate healing of any local cytotoxic effects in the tumor or surrounding tissue.

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ISE 3.1.2.1

Preparation Instructions: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Aseptic techniques should be employed during preparation of IntraDose. Precautions appropriate for the handling of antineoplastic agents should be exercised including preparation under a laminar flow hood (see DOSAGE AND ADMINISTRATION; Storage and Handling).

Needles containing aluminum parts that may come in contact with IntraDose should not be used for preparation or administration. Aluminum reacts with cisplatin, causing precipitate formation and a loss of potency.

Platinol Package Insert

No components of the kits should be substituted.

Remove kit from refrigerator and allow to warm to room temperature for at least 5 minutes.

Attach the sterile 22-gauge needle provided in the kit to the empty sterile 3-cc syringe. Withdraw 1.7 mL of IntraEpi (epinephrine solution), and transfer into the vial of IntraPlatin (cisplatin for injectable suspension). Discard the IntraEpi vial and remaining contents.

Swirl the IntraPlatin vial for 30 seconds to yield a homogeneous suspension. Invert the vial and, while gently swirling, withdraw 1.5 mL of the reconstituted IntraPlatin suspension into the 3-cc syringe. Remove and discard the needle upon completion of withdrawal.

Remove the IntraGel syringe from the kit, remove its rubber tip cap and attach the Luer-lock syringe connector.

Attach the syringe containing the IntraPlatin suspension on the syringe connector attached to the IntraGel syringe. Make sure the connections are secure and then slowly transfer the suspension into the IntraGel syringe. Pushing the plunger gently will eject the outer stopper from the IntraGel syringe. Affix the plunger rod into the IntraGel syringe by placing the threaded end into the syringe barrel and screwing it gently into the inner (remaining) rubber plunger. With both syringes securely fastened to the syringe connector, rapidly transfer the contents back and forth between syringes for 30 seconds (30 strokes forward and 30 strokes backward) to effect complete mixing.

Complete the mixing with all the contents in the 3-cc (plastic) syringe. Remove and discard the empty glass syringe and Luer-lock syringe connector; then attach a suitable sterile administration needle to the 3-cc syringe containing the final mixed IntraDose Injectable Gel. The needle for patient injection is not included in the IntraDose kit.

Preparation as specified results in 2 mL of a viscous, opaque, pale yellow gel containing 8.0 mg of cisplatin and 0.2 mg of epinephrine.

NOTE: Discard 4 hours after mixing.

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Using a small (22 to 25 gauge) needle attached to a Luer-lock syringe, insert the needle into the base of the tumor at approximately a 45-degree angle. Pull back gently on the plunger. If blood appears, withdraw the needle and repeat. If blood does not appear, proceed with administration. Depending on the size and location of the tumor, the injection may be done by tracking the product through the tumor from a single puncture site or by injecting the tumor from multiple sites in parallel rows approximately 0.5 to 1.0 cm apart.