Navelbine Injection

vinorelbine tartrate

Dosage Form: injection
NAVELBINE® (vinorelbine tartrate) Injection

Warning

NAVELBINE (vinorelbine tartrate) Injection should be administered under the supervision of a physician experienced in the use of cancer chemotherapeutic agents. This product is for intravenous (IV) use only. Intrathecal administration of other vinca alkaloids has resulted in death. Syringes containing this product should be labeled "WARNING - FOR IV USE ONLY. FATAL if given intrathecally."

Severe granulocytopenia resulting in increased susceptibility to infection may occur. Granulocyte counts should be ≥1,000 cells/mm3 prior to the administration of NAVELBINE. The dosage should be adjusted according to complete blood counts with differentials obtained on the day of treatment.

Caution - It is extremely important that the intravenous needle or catheter be properly positioned before NAVELBINE is injected. Administration of NAVELBINE may result in extravasation causing local tissue necrosis and/or thrombophlebitis (see DOSAGE AND ADMINISTRATION: Administration Precautions).

Navelbine Injection Description

NAVELBINE (vinorelbine tartrate) Injection is for intravenous administration. Each vial contains vinorelbine tartrate equivalent to 10 mg (1-mL vial) or 50 mg (5-mL vial) in Water for Injection. No preservatives or other additives are present. The aqueous solution is sterile and nonpyrogenic. Vinorelbine tartrate is a semi-synthetic vinca alkaloid with antitumor activity.

The chemical name is 3',4'-didehydro-4'-deoxy-C'-norvincaleukoblastine [R-(R*,R*)-2, 3-dihydroxybutanedioate (1:2)(salt)].

Vinorelbine tartrate has the following structure:

vinorelbine tartrate is a white to yellow or light brown amorphous powder with the molecular formula C45H54N4O8•2C4H6O6 and molecular weight of 1079.12. The aqueous solubility is >1,000 mg/mL in distilled water. The pH of Navelbine Injection is approximately 3.5.

Navelbine Injection - Clinical Pharmacology

Vinorelbine is a vinca alkaloid that interferes with microtubule assembly. The vinca alkaloids are structurally similar compounds comprised of 2 multiringed units, vindoline and catharanthine. Unlike other vinca alkaloids, the catharanthine unit is the site of structural modification for vinorelbine. The antitumor activity of vinorelbine is thought to be due primarily to inhibition of mitosis at metaphase through its interaction with tubulin. Like other vinca alkaloids, vinorelbine may also interfere with: 1) amino acid, cyclic AMP, and glutathione metabolism, 2) calmodulin-dependent Ca++-transport ATPase activity, 3) cellular respiration, and 4) nucleic acid and lipid biosynthesis. In intact tectal plates from mouse embryos, vinorelbine, vincristine and vinblastine inhibited mitotic microtubule formation at the same concentration (2 µM), inducing a blockade of cells at metaphase. Vincristine produced depolymerization of axonal microtubules at 5 µM, but vinblastine and vinorelbine did not have this effect until concentrations of 30 µM and 40 µM, respectively. These data suggest relative selectivity of vinorelbine for mitotic microtubules.

Pharmacokinetics

The pharmacokinetics of vinorelbine were studied in 49 patients who received doses of 30 mg/m2 in 4 clinical trials. Doses were administered by 15- to 20-minute constant-rate infusions. Following intravenous administration, vinorelbine concentration in plasma decays in a triphasic manner. The initial rapid decline primarily represents distribution of drug to peripheral compartments followed by metabolism and excretion of the drug during subsequent phases. The prolonged terminal phase is due to relatively slow efflux of vinorelbine from peripheral compartments. The terminal phase half-life averages 27.7 to 43.6 hours and the mean plasma clearance ranges from 0.97 to 1.26 L/hr/kg. Steady-state volume of distribution (VSS) values range from 25.4 to 40.1 L/kg.

Vinorelbine demonstrated high binding to human platelets and lymphocytes. The free fraction was approximately 0.11 in pooled human plasma over a concentration range of 234 to 1,169 ng/mL. The binding to plasma constituents in cancer patients ranged from 79.6% to 91.2%. Vinorelbine binding was not altered in the presence of cisplatin, 5-fluorouracil, or doxorubicin.

Vinorelbine undergoes substantial hepatic elimination in humans, with large amounts recovered in feces after intravenous administration to humans. Two metabolites of vinorelbine have been identified in human blood, plasma, and urine; vinorelbine N-oxide and deacetylvinorelbine. Deacetylvinorelbine has been demonstrated to be the primary metabolite of vinorelbine in humans, and has been shown to possess antitumor activity similar to vinorelbine. Therapeutic doses of vinorelbine (30 mg/m2) yield very small, if any, quantifiable levels of either metabolite in blood or urine. The metabolism of vinca alkaloids has been shown to be mediated by hepatic cytochrome P450 isoenzymes in the CYP3A subfamily. This metabolic pathway may be impaired in patients with hepatic dysfunction or who are taking concomitant potent inhibitors of these isoenzymes (see PRECAUTIONS).

The effects of renal or hepatic dysfunction on the disposition of vinorelbine have not been assessed, but based on experience with other anticancer vinca alkaloids, dose adjustments are recommended for patients with impaired hepatic function (see DOSAGE AND ADMINISTRATION).

The disposition of radiolabeled vinorelbine given intravenously was studied in a limited number of patients. Approximately 18% and 46% of the administered dose was recovered in the urine and in the feces, respectively. Incomplete recovery in humans is consistent with results in animals where recovery is incomplete, even after prolonged sampling times.

A separate study of the urinary excretion of vinorelbine using specific chromatographic analytical methodology showed that 10.9% ± 0.7% of a 30-mg/m2 intravenous dose was excreted unchanged in the urine.

The influence of age on the pharmacokinetics of vinorelbine was examined using data from 44 cancer patients (average age, 56.7 ± 7.8 years; range, 41 to 74 years; with 12 patients ≥60 years and 6 patients ≥65 years) in 3 studies. CL (the mean plasma clearance), t1/2 (the terminal phase half-life), and Vz (the volume of distribution during terminal phase) were independent of age. A separate pharmacokinetic study was conducted in 10 elderly patients with metastatic breast cancer (age range, 66 to 81 years; 3 patients >75 years; normal liver function tests) receiving vinorelbine 30 mg/m2 intravenously. CL, Vss, and t1/2 were similar to those reported for younger adult patients in previous studies. No relationship between age, systemic exposure (AUC0-∞), and hematological toxicity was observed.

The pharmacokinetics of vinorelbine are not influenced by the concurrent administration of cisplatin with NAVELBINE (see PRECAUTIONS: Drug Interactions).

Clinical Trials

Data from 1 randomized clinical study (211 evaluable patients) with single-agent NAVELBINE and 2 randomized clinical trials (1,044 patients) using NAVELBINE combined with cisplatin support the use of NAVELBINE in patients with advanced non-small cell lung cancer (NSCLC).

Single-Agent NAVELBINE

Single-agent NAVELBINE was studied in a North American, randomized clinical trial in which patients with Stage IV NSCLC, no prior chemotherapy, and Karnofsky Performance Status ≥70 were treated with NAVELBINE (30 mg/m2) weekly or 5-fluorouracil (5-FU) (425 mg/m2 IV bolus) plus leucovorin (LV) 20 mg/m2 IV bolus) daily for 5 days every 4 weeks. A total of 211 patients were randomized at a 2:1 ratio to NAVELBINE (143) or 5-FU/LV (68). NAVELBINE showed improved survival time compared to 5-FU/LV.

In an intent-to-treat analysis, the median survival time was 30 weeks versus 22 weeks for patients receiving NAVELBINE versus 5-FU/LV, respectively (P=0.06). The 1-year survival rates were 24% (±4% SE) for NAVELBINE and 16% (±5% SE) for the 5-FU/LV group, using the Kaplan-Meier product-limit estimates. The median survival time with 5-FU/LV was similar to or slightly better than that usually observed in untreated patients with advanced NSCLC, suggesting that the difference was not related to some unknown detrimental effect of 5-FU/LV therapy. The response rates (all partial responses) for NAVELBINE and 5-FU/LV were 12% and 3%, respectively.

NAVELBINE in Combination with Cisplatin: NAVELBINE plus Cisplatin versus Single-Agent Cisplatin

A Phase III open-label, randomized study was conducted which compared NAVELBINE (25 mg/m2/week) plus cisplatin (100 mg/m2 every 4 weeks) to single-agent cisplatin (100 mg/m2 every 4 weeks) in patients with Stage IV or Stage IIIb NSCLC patients with malignant pleural effusion or multiple lesions in more than one lobe who were not previously treated with chemotherapy. Patients included in the study had a performance status of 0 or 1, and 34% had received prior surgery and/or radiotherapy. Characteristics of the 432 randomized patients are provided in Table 1. Two hundred and twelve patients received NAVELBINE plus cisplatin and 210 received single-agent cisplatin. The primary objective of this trial was to compare survival between the 2 treatment groups. Survival (Figure 1) for patients receiving NAVELBINE plus cisplatin was significantly better compared to the patients who received single-agent cisplatin. The results of this trial are summarized in Table 1

NAVELBINE plus Cisplatin versus Vindesine plus Cisplatin versus Single-Agent NAVELBINE

In a large European clinical trial, 612 patients with Stage III or IV NSCLC, no prior chemotherapy, and WHO Performance Status of 0, 1, or 2 were randomized to treatment with single-agent NAVELBINE (30 mg/m2/week), NAVELBINE (30 mg/m2/week) plus cisplatin (120 mg/m2 days 1 and 29, then every 6 weeks), and vindesine (3 mg/m2/week for 7 weeks, then every other week) plus cisplatin (120 mg/m2 days 1 and 29, then every 6 weeks). Patient characteristics are provided in Table 1. Survival was longer in patients treated with NAVELBINE plus cisplatin compared to those treated with vindesine plus cisplatin (Figure 2). Study results are summarized in Table 1.

Dose-Ranging Study

A dose-ranging study of NAVELBINE (20, 25, or 30 mg/m2/week) plus cisplatin (120 mg/m2 days 1 and 29, then every 6 weeks) in 32 patients with NSCLC demonstrated a median survival of 10.2 months. There were no responses at the lowest dose level; the response rate was 33% in the 21 patients treated at the 2 highest dose levels.

Table 1: Randomized Clinical Trials of NAVELBINE in Combination with Cisplatin in NSCLC

	NAVELBINE Cisplatin vs. Single-Agent Cisplatin		NAVELBINE/Cisplatin vs. Vindesine/Cisplatin vs. Single-Agent NAVELBINE
	NAVELBINE/ Cisplatin	Cisplatin	NAVELBINE/ Cisplatin	Vindesine/ Cisplatin	NAVELBINE
Demographics    Number of patients    Number of males    Number of females	214 146 68	218 141 77	206 182 24	200 179 21	206 188 18
Median age (years) Range (years)	63 33-84	64 37-81	59 32-75	59 31-75	60 30-74
Stage of disease    Stage IIIA    Stage IIIB    Stage IV    Local recurrence    Metastatic after surgery	NA 8% 92% NA NA	NA 8% 92% NA NA	11% 28% 50% 2% 9%	11% 25% 55% 3% 8%	10% 32% 47% 3 % 9 %
Histology    Adenocarcinoma    Squamous    Large cell    Unspecified	54% 19% 14% 13%	52% 22% 14 % 13%	32% 56% 13% NA	40% 50% 11% NA	28% 56% 16% NA
Results    Median survival (months)	7.8	6.2	9.2*†	7.4	7.2
P value	P = 0.01		*P = 0.09 vs. vindesine/cisplatin † = 0.05 vs. single-agent NAVELBINE
12-Month survival rate	38%	22%	35%	27%	30%
Overall response	19%	8%	28%‡§	19%	14%
P value	P<0.001		‡P = 0.03 vs. vindesine/cisplatin §P<0.001 vs. single-agent NAVELBINE

Indications and Usage for Navelbine Injection

NAVELBINE is indicated as a single agent or in combination with cisplatin for the first-line treatment of ambulatory patients with unresectable, advanced non-small cell lung cancer (NSCLC). In patients with Stage IV NSCLC, NAVELBINE is indicated as a single agent or in combination with cisplatin. In Stage III NSCLC, NAVELBINE is indicated in combination with cisplatin

Contraindications

Administration of NAVELBINE is contraindicated in patients with pretreatment granulocyte counts <1,000 cells/mm3 (see WARNINGS).

Warnings

NAVELBINE should be administered in carefully adjusted doses by or under the supervision of a physician experienced in the use of cancer chemotherapeutic agents. Patients treated with NAVELBINE should be frequently monitored for myelosuppression both during and after therapy. Granulocytopenia is dose-limiting. Granulocyte nadirs occur between 7 and 10 days after dosing with granulocyte count recovery usually within the following 7 to 14 days. Complete blood counts with differentials should be performed and results reviewed prior to administering each dose of NAVELBINE. NAVELBINE should not be administered to patients with granulocyte counts <1,000 cells/mm3. Patients developing severe granulocytopenia should be monitored carefully for evidence of infection and/or fever. See DOSAGE AND ADMINISTRATION for recommended dose adjustments for granulocytopenia. Acute shortness of breath and severe bronchospasm have been reported infrequently, following the administration of NAVELBINE and other vinca alkaloids, most commonly when the vinca alkaloid was used in combination with mitomycin. These adverse events may require treatment with supplemental oxygen, bronchodilators, and/or corticosteroids, particularly when there is pre-existing pulmonary dysfunction. Reported cases of interstitial pulmonary changes and acute respiratory distress syndrome (ARDS), most of which were fatal, occurred in patients treated with single-agent NAVELBINE. The mean time to onset of these symptoms after vinorelbine administration was 1 week (range 3 to 8 days). Patients with alterations in their baseline pulmonary symptoms or with new onset of dyspnea, cough, hypoxia, or other symptoms should be evaluated promptly.

NAVELBINE has been reported to cause severe constipation (e.g., Grade 3-4), paralytic ileus, intestinal obstruction, necrosis, and/or perforation. Some events have been fatal.

Pregnancy

Pregnancy Category D. NAVELBINE may cause fetal harm if administered to a pregnant woman. A single dose of vinorelbine has been shown to be embryo- and/or fetotoxic in mice and rabbits at doses of 9 mg/m2 and 5.5 mg/m2, respectively (one third and one sixth the human dose). At nonmaternotoxic doses, fetal weight was reduced and ossification was delayed. There are no studies in pregnant women. If NAVELBINE is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant during therapy with NAVELBINE.

Precautions

General

Most drug-related adverse events of NAVELBINE are reversible. If severe adverse events occur, NAVELBINE should be reduced in dosage or discontinued and appropriate corrective measures taken. Reinstitution of therapy with NAVELBINE should be carried out with caution and alertness as to possible recurrence of toxicity. NAVELBINE should be used with extreme caution in patients whose bone marrow reserve may have been compromised by prior irradiation or chemotherapy, or whose marrow function is recovering from the effects of previous chemotherapy (see DOSAGE AND ADMINISTRATION). Administration of NAVELBINE to patients with prior radiation therapy may result in radiation recall reactions (see ADVERSE REACTIONS and Drug Interactions). Patients with a prior history or pre-existing neuropathy, regardless of etiology, should be monitored for new or worsening signs and symptoms of neuropathy while receiving NAVELBINE.

Care must be taken to avoid contamination of the eye with concentrations of NAVELBINE used clinically. Severe irritation of the eye has been reported with accidental exposure to another vinca alkaloid. If exposure occurs, the eye should immediately be thoroughly flushed with water.

Information for Patients

Patients should be informed that the major acute toxicities of NAVELBINE are related to bone marrow toxicity, specifically granulocytopenia with increased susceptibility to infection. They should be advised to report fever or chills immediately. Women of childbearing potential should be advised to avoid becoming pregnant during treatment. Patients should be advised to contact their physician it they experience increased shortness of breath, cough, or other new pulmonary symptoms, or if they experience symptoms of abdominal pain or constipation.

Laboratory Tests

Since dose-limiting clinical toxicity is the result of depression of the white blood cell count, it is imperative that complete blood counts with differentials be obtained and reviewed on the day of treatment prior to each dose of NAVELBINE (see ADVERSE REACTIONS: Hematologic).

Hepatic

There is no evidence that the toxicity of NAVELBINE is enhanced in patients with elevated liver enzymes. No data are available for patients with severe baseline cholestasis, but the liver plays an important role in the metabolism of NAVELBINE. Because clinical experience in patients with severe liver disease is limited, caution should be exercised when administering NAVELBINE to patients with severe hepatic injury or impairment (see DOSAGE AND ADMINISTRATION).

Drug Interactions

Acute pulmonary reactions have been reported with NAVELBINE and other anticancer vinca alkaloids used in conjunction with mitomycin. Although the pharmacokinetics of vinorelbine are not influenced by the concurrent administration of cisplatin, the incidence of granulocytopenia with NAVELBINE used in combination with cisplatin is significantly higher than with single-agent NAVELBINE. Patients who receive NAVELBINE and paclitaxel, either concomitantly or sequentially, should be monitored for signs and symptoms of neuropathy. Administration of NAVELBINE to patients with prior or concomitant radiation therapy may result in radio sensitizing effects. Caution should be exercised in patients concurrently taking drugs known to inhibit drug metabolism by hepatic cytochrome P450 isoenzymes in the CYP3A subfamily, or in patients with hepatic dysfunction. Concurrent administration of vinorelbine tartrate with an inhibitor of this metabolic pathway may cause an earlier onset and/or an increased severity of side effects.

Carcinogenesis, Mutagenesis, Impairment of Fertility

The carcinogenic potential of NAVELBINE has not been studied. Vinorelbine has been shown to affect chromosome number and possibly structure in vivo (polyploidy in bone marrow cells from Chinese hamsters and a positive micronucleus test in mice). It was not mutagenic in the Ames test and gave inconclusive results in the mouse lymphoma TK Locus assay. The significance of these or other short-term test results for human risk is unknown. Vinorelbine did not affect fertility to a statistically significant extent when administered to rats on either a once-weekly (9 mg/m2, approximately one third the human dose) or alternate-day schedule (4.2 mg/m2, approximately one seventh the human dose) prior to and during mating. However, biweekly administration for 13 or 26 weeks in the rat at 2.1 and 7.2 mg/m2 (approximately one fifteenth and one fourth the human dose) resulted in decreased spermatogenesis and prostate/seminal vesicle secretion.

Pregnancy

Pregnancy Category D. See WARNINGS section.

Nursing Mothers

It is not known whether the 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 NAVELBINE, it is recommended that nursing be discontinued in women who are receiving therapy with NAVELBINE.

Pediatric Use

Safety and effectiveness of NAVELBINE in pediatric patients have not been established. Data from a single-arm study in 46 patients with recurrent solid malignant tumors, including rhabdomyosarcoma/undifferentiated sarcoma, neuroblastoma, and CNS tumors, at doses similar to those used in adults, showed no meaningful clinical activity. Toxicities were similar to those reported in adults.

Geriatric Use

Of the total number of patients in North American clinical studies of IV NAVELBINE, approximately one third were 65 years of age or greater. No overall differences in effectiveness or safety were observed between these patients and younger adult patients. Other reported clinical experience has not identified differences in responses between the elderly and younger adult patients, but greater sensitivity of some older individuals cannot be ruled out.

The pharmacokinetics of vinorelbine in elderly and younger adult patients are similar (see CLINICAL PHARMACOLOGY).

Adverse Reactions

The pattern of adverse reactions is similar whether NAVELBINE is used as a single agent or in combination. Adverse reactions from studies with single-agent and combination use of NAVELBINE are summarized in Tables 2-4.

Single-Agent NAVELBINE

Data in the following table are based on the experience of 365 patients (143 patients with NSCLC; 222 patients with advanced breast cancer) treated with IV NAVELBINE as a single agent in 3 clinical studies. The dosing schedule in each study was 30 mg/m2NAVELBINE on a weekly basis.

Table 2: Summary of Adverse Events in 365 Patients Receiving Single-Agent NAVELBINE*†:

Adverse Event			All Patients (n=365)	NSCLC (n=143)
Bone Marrow
Granulocytopenia	<2,000 cells/mm3		90%	80%
	<500 cells/mm3		36%	29%
Leukopenia	<4,000 celIs/mm3		92%	81%
	<1,000 cells/mm3		15%	12%
Thrombocytopenia	<100,000 cells/mm3		5%	4%
	<50,000 cells/mm3		1%	1%
Anemia	<11 g/dL		83%	77%
	<8 g/dL		9%	1%
Hospitalizations due to granulocytopenic complications			9%	8%

Table 2: Summary of Adverse Events in 365 Patients Receiving Single-Agent NAVELBINE*†:

* None of the reported toxicities were influenced by age. Grade based on modified criteria from the National Cancer Institute. † Patients with NSCLC had not received prior chemotherapy. The majority of the remaining patients had received prior chemotherapy. ‡ Incidence of paresthesia plus hypesthesia.
	All Grades		Grade 3		Grade 4
	All Patients	NSCLC	All Patients	NSCLC	All Patients	NSCLC
Clinical Chemistry
Elevations
Total Bilirubin (n=351)	13%	9%	4%	3%	3%	2%
SGOT (n=346)	67%	54%	5%	2%	1%	1%
General
Asthenia	36%	27%	7%	5%	0%	0%
Injection Site Reactions	28%	38%	2%	5%	0%	0%
Injection Site Pain	16%	13%	2%	1%	0%	0%
Phlebitis	7%	10%	<1%	1%	0%	0%
Digestive
Nausea	44%	34%	2%	1%	0%	0%
Vomiting	20%	15%	2%	1%	0%	0%
Constipation	35%	29%	3%	2%	0%	0%
Diarrhea	17%	13%	1%	1%	0%	0%
Peripheral Neuropathy‡	25%	20%	1%	1%	<1%	0%
Dyspnea	7%	3%	2%	2%	1%	0%
Alopecia	12%	12%	<1%	1%	0%	0%

Hematologic

Granulocytopenia is the major dose-limiting toxicity with NAVELBINE. Dose adjustments are required for hematologic toxicity and hepatic insufficiency (see DOSAGE AND ADMINISTRATION). Granulocytopenia was generally reversible and not cumulative over time. Granulocyte nadirs occurred 7 to 10 days after the dose, with granulocyte recovery usually within the following 7 to 14 days. Granulocytopenia resulted in hospitalizations for fever and/or sepsis in 8% of patients. Septic deaths occurred in approximately 1% of patients. Prophylactic hematologic growth factors have not been routinely used with NAVELBINE.

If medically necessary, growth factors may be administered at recommended doses no earlier than 24 hours after the administration of cytotoxic chemotherapy. Growth factors should not be administered in the period 24 hours before the administration of chemotherapy. Whole blood and/or packed red blood cells were administered to 18% of patients who received NAVELBINE.

Neurologic

Loss of deep tendon reflexes occurred in less than 5% of patients. The development of severe peripheral neuropathy was infrequent (1%) and generally reversible.

Skin

Like other antirancer vinca alkaloids, NAVELBINE is a moderate vesicant. Injection site reactions, including erythema, pain at injection site, and vein discoloration, occurred in approximately one third of patients; 5% were severe. Chemical phlebitis along the vein proximal to the site of injection was reported in 10% of patients.

Gastrointestinal

Prophylactic administration of antiemetics was not routine in patients treated with single-agent NAVELBINE. Due to the low incidence of severe nausea and vomiting with single-agent NAVELBINE, the use of serotonin antagonists is generally not required.

Hepatic

Transient elevations of liver enzymes were reported without clinical symptoms.

Cardiovascular

Chest pain was reported in 5% of patients. Most reports of chest pain were in patients who had either a history of cardiovascular disease or tumor within the chest. There have been rare reports of myocardial infarction.

Pulmonary

Shortness of breath was reported in 3% of patients; it was severe in 2% (see WARNINGS). Interstitial pulmonary changes were documented.

Other

Fatigue occurred in 27% of patients. It was usually mild or moderate but tended to increase with cumulative dosing.

Other toxicities that have been reported in less than 5% of patients include jaw pain, myalgia, arthralgia, and rash. Hemorrhagic cystitis and the syndrome of inappropriate ADH secretion were each reported in <1% of patients.

Combination Use

Adverse events for combination use are summarized in Tables 3 and 4.

NAVELBINE in Combination with Cisplatin

NAVELBINE plus Cisplatin versus Single-Agent Cisplatin (Table 3): Myelosuppression was the predominant toxicity in patients receiving combination therapy, Grade 3 and 4 granulocytopenia of 82% compared to 5% in the single-agent cisplatin arm. Fever and/or sepsis related to granulocytopenia occurred in 11% of patients on NAVELBINE and cisplatin compared to 0% on the cisplatin arm. Four patients on the combination died of granulocytopenia-related sepsis. During this study, the use of granulocyte colony-stimulating factor ([G-CSF] filgrastim) was permitted, but not mandated, after the first course of treatment for patients who experienced Grade 3 or 4 granulocytopenia (x1,000 cells/mm3) or in those who developed neutropenic fever between cycles of chemotherapy. Beginning 24 hours after completion of chemotherapy, G-CSF was started at a dose of 5 mcg/kg per day and continued until the total granulocyte count was >1,000 cells/mm3 on 2 successive determinations. G-CSF was not administered on the day of treatment. Grade 3 and 4 anemia occurred more frequently in the combination arm compared to control, 24% vs. 8%, respectively. Thrombocytopenia occurred in 6% of patients treated with NAVELBINE plus cisplatin compared to 2% of patients treated with cisplatin. The incidence of severe non-hematologic toxicity was similar among the patients in both treatment groups. Patients receiving NAVELBINE plus cisplatin compared to single-agent cisplatin experienced more Grade 3 and/or 4 peripheral numbness (2% vs. <1%), phlebitis/thrombosis/embolism (3% vs. <1%), and infection (6% vs. <1%). Grade 3-4 constipation and/or ileus occurred in 3% of patients treated with combination therapy and in 1% of patients treated with cisplatin. Seven deaths were reported on the combination arm; 2 were related to cardiac ischemia, 1 massive cerebrovascular accident, 1 multisystem failure due to an overdose of NAVELBINE, and 3 from febrile neutropenia. One death, secondary to respiratory infection unrelated to granulocytopenia, occurred with single-agent cisplatin.

NAVELBINE plus Cisplatin versus Vindesine plus Cisplatin versus Single-Agent Vinorelbine (Table 4)

Myelosuppression, specifically Grade 3 and 4 granulocytopenia, was significantly greater with the combination of NAVELBINE plus cisplatin (79%) than with either single-agent NAVELBINE (53%) or vindesine plus cisplatin (48%), P<0.0001. Hospitalization due to documented sepsis occurred in 4.4% of patients treated with NAVELBINE plus cisplatin: 2% of patients treated with vindesine and cisplatin, and 4% of patients treated with single-agent NAVELBINE. Grade 3 and 4 thrombocytopenia was infrequent in patients receiving combination chemotherapy and no events were reported with single-agent NAVELBINE.

The incidence of Grade 3 and/or 4 nausea and vomiting, alopecia, and renal toxicity were reported more frequently in the cisplatin-containing combinations compared to single-agent NAVELBINE. Severe localNAVELBINE® (vinorelbine tartrate) Injection reactions occurred in 2% of patients treated with combinations containing NAVELBINE; none were observed in the vindesine plus cisplatin arm. Grade 3 and 4 neurotoxicity was significantly more frequent in patients receiving vindesine plus cisplatin (17%) comparedto NAVELBINE plus cisplatin (7%) and single-agent vinorelbine (9%) (P<0.005). Cisplatin did not appear to increase the incidence of neurotoxicity observed with single-agent NAVELBINE.

Table 3: Selected Adverse Events From a Comparative Trial of NAVELBINE plus Cisplatin versus Single-Agent Cisplatin*

*Graded according to the standard SWOG criteria.
	NAVELBINE 25 mg/m2 plus Cisplatin 100 mg/m2 (n=212)			Cisplatin 100 mg/m2 (n=210)
Adverse Event	All Grades	Grade 3	Grade 4	All Grades	Grade 3	Grade 4
Bone Marrow
Granulocytopenia	89%	22%	60%	26%	4%	1%
Anemia	88%	21%	3%	72%	7%	<1%
Leukopenia	88%	39%	19%	31%	<1%	0%
Thrombocytopenia	29%	4%	1%	21%	1%	<1%
Febrile neutropenia	N/A	N/A	11%	N/A	N/A	0%
Hepatic
Elevated transaminase	1%	0%	0%	<1%	<1%	0%
Renal
Elevated creatinine	37%	2%	2%	28%	4%	<1%
Non-Laboratory
Malaise/fatigue/lethargy	67%	12%	0%	49%	8%	0%
Vomiting	60%	7%	6%	60%	10%	4%
Nausea	58%	14%	0%	57%	12%	0%
Anorexia	46%	0%	0%	37%	0%	0%
Constipation	35%	3%	0%	16%	1%	0%
Alopecia	34%	0%	0%	14%	0%	0%
Weight loss	34%	1%	0%	21%	<1%	0%
Fever without infection	20%	2%	0%	4%	0%	0%
Hearing	18%	4%	0%	18%	3%	<1%
Local (injection site reactions)	17%	<1%	0%	1%	0%	0%
Diarrhea	17%

Acyclovir Injection

Dosage Form: injection, powder, for solution
Acyclovir Sodium Injection

FOR INTRAVENOUS INFUSION ONLY

Acyclovir Injection Description

Acyclovir Sodium Injection is a synthetic nucleoside analog, active against herpes viruses.  It is a sterile, aqueous solution for intravenous infusion, containing 50 mg acyclovir per mL in Water for Injection, USP.  The concentration is equivalent to 54.9 mg of acyclovir sodium per mL in Water for Injection, USP.  The sodium content is approximately 5.1 mg/mL.  The pH range of the solution is 10.85 to 11.50.  Further dilution of Acyclovir Sodium Injection in an appropriate intravenous solution must be performed before infusion (see DOSAGE AND ADMINISTRATION, Administration).

The chemical name of acyclovir sodium is 9-[(2-Hydroxyethoxy)methyl] guanine, and has the following structural formula:

 

 

Acyclovir sodium is a white, crystalline powder with the molecular formula C8H10N5NaO3 and a molecular weight of 247.19.  The maximum solubility in water at 25°C exceeds 100 mg/mL.  At physiologic pH, acyclovir sodium exists as the unionized form with a molecular weight of 225 and a maximum solubility in water at 37°C of 2.5 mg/mL.  The pka’s of acyclovir are 2.27 and 9.25.

VIROLOGY

Mechanism of Antiviral Action

Acyclovir is a synthetic purine nucleoside analogue with in vitro and in vivo inhibitory activity against herpes simplex virus types 1 (HSV-1), 2 (HSV-2) and varicella-zoster virus (VZV).

The inhibitory activity of acyclovir is highly selective due to its affinity for the enzyme thymidine kinase (TK) encoded by HSV and VZV.  This viral enzyme converts acyclovir into acyclovir monophosphate, a nucleotide analogue.  The monophosphate is further converted into diphosphate by cellular guanylate kinase and into triphosphate by a number of cellular enzymes.  In vitro, acyclovir triphosphate stops replication of herpes viral DNA.  This is accomplished in three ways: 1) competitive inhibition of viral DNA polymerase, 2) incorporation into and termination of the growing viral DNA chain, and 3) inactivation of the viral DNA polymerase.  The greater antiviral activity of acyclovir against HSV compared to VZV is due to its more efficient phosphorylation by the viral TK.

Antiviral Activities

The quantitative relationship between the in vitro susceptibility of herpes viruses to antivirals and the clinical response to therapy has not been established in humans, and virus sensitivity testing has not been standardized.  Sensitivity testing results, expressed as the concentration of drug required to inhibit by 50% the growth of virus in cell culture (IC50), vary greatly depending upon a number of factors.  Using plaque-reduction assays, the IC50 against herpes simplex virus isolates ranges from 0.02 to 13.5 mcg/mL for HSV-1 and from 0.01 to 9.9 mcg/mL for HSV-2.  The IC50 for acyclovir against most laboratory strains and clinical isolates of VZV ranges from 0.12 to 10.8 mcg/mL.  Acyclovir also demonstrates activity against the Oka vaccine strain of VZV with a mean IC50 of 1.35 mcg/mL.

Drug Resistance

Resistance of HSV and VZV to acyclovir can result from qualitative or quantitative changes in the viral TK and/or DNA polymerase.  Clinical isolates of HSV and VZV with reduced susceptibility to acyclovir have been recovered from immunocompromised patients, especially with advanced HIV infection.  While most of the acyclovir-resistant mutants isolated thus far from such patients have been found to be TK-deficient mutants, other mutants involving the viral TK gene (TK partial and TK altered) and DNA polymerase have been isolated.  TK-negative mutants may cause severe disease in infants and immunocompromised adults.  The possibility of viral resistance to acyclovir should be considered in patients who show poor clinical response during therapy.

Acyclovir Injection - Clinical Pharmacology

Pharmacokinetics

The pharmacokinetics of acyclovir after intravenous administration have been evaluated in adult patients with normal renal function during Phase 1/2 studies after single doses ranging from 0.5 to 15 mg/kg and after multiple doses ranging from 2.5 to 15 mg/kg every 8 hours.  Proportionality between dose and plasma levels is seen after single doses or at steady-state after multiple dosing.  Average steady-state peak and trough concentrations from 1-hour infusions administered every 8 hours are given in Table 1.

Table 1: Acyclovir Peak and Trough Concentrations

                          at Steady-State

Dosage Regimen	CSSmax	CSStrough
5 mg/kg q 8 h (n=8)	9.8 mcg/mL range: 5.5 to 13.8	0.7 mcg/mL range: 0.2 to 1
10 mg/kg q 8 h (n=7)	22.9 mcg/mL range: 14.1 to 44.1	1.9 mcg/mL range: 0.5 to 2.9

Concentrations achieved in the cerebrospinal fluid are approximately 50% of plasma values.  Plasma protein binding is relatively low (9% to 33%) and drug interactions involving binding site displacement are not anticipated.

Renal excretion of unchanged drug is the major route of acyclovir elimination accounting for 62% to 91% of the dose.  The only major urinary metabolite detected is 9-carboxymethoxymethylguanine accounting for up to 14.1% of the dose in patients with normal renal function.

The half-life and total body clearance of acyclovir are dependent on renal function as shown in Table 2.

 

      Table 2: Acyclovir Half-life and Total Body Clearance

Creatinine Clearance (mL/min/1.73 m2)		Total Body Clearance
	Half-Life (hr)	(mL/min/1.73 m2)	(mL/min/kg)
>80 50-80 15-50 0 (Anuric)	2.5 3 3.5 19.5	327 248 190 29	5.1 3.9 3.4 0.5

Special Populations

Adults With Impaired Renal Function

Acyclovir was administered at a dose of 2.5 mg/kg to 6 adult patients with severe renal failure.  The peak and trough plasma levels during the 47 hours preceding hemodialysis were 8.5 mcg/mL and 0.7 mcg/mL, respectively.

Consult DOSAGE AND ADMINISTRATION section for recommended adjustments in dosing based upon creatinine clearance.

 

Pediatrics

Acyclovir pharmacokinetics were determined in 16 pediatric patients with normal renal function ranging in age from 3 months to 16 years at doses of approximately 10 mg/kg and 20 mg/kg every 8 hours (Table 3).  Concentrations achieved at these regimens are similar to those in adults receiving 5 mg/kg and 10 mg/kg every 8 hours, respectively (Table 1).  Acyclovir pharmacokinetics were determined in 12 patients ranging in age from birth to 3 months at doses of 5 mg/kg, 10 mg/kg, and 15 mg/kg every 8 hours (Table 3).

 

        Table 3: Acyclovir Pharmacokinetics in Pediatric Patients (Mean ± SD)

Parameter	Birth to 3 Months of Age (n=12)	3 Months to 12 Years of Age (n=16)
CL (mL/min/kg)	4.46 ± 1.61	8.44 ± 2.92
VDSS (L/kg)	1.08 ± 0.35	1.01 ± 0.28
Elimination half-life (hours)	3.80 ± 1.19	2.36 ± 0.97

Geriatrics

Acyclovir plasma concentrations are higher in geriatric patients compared to younger adults, in part due to age-related changes in renal function.  Dosage reduction may be required in geriatric patients with underlying renal impairment (see PRECAUTIONS: Geriatric Use).

Drug Interactions

Coadministration of probenecid with acyclovir has been shown to increase the mean acyclovir half-life and the area under the concentration-time curve.  Urinary excretion and renal clearance were correspondingly reduced.

CLINICAL TRIALS

Herpes Siplex Infections in Immuocompromised Patients

A multicenter trial of acyclovir at a dose of 250 mg/m2 every 8 hours (750 mg/m2/day) for 7 days was conducted in 98 immunocompromised patients (73 adults and 25 children) with orofacial, esophageal, genital and other localized infections (52 treated with acyclovir and 46 with placebo).  Acyclovir decreased virus excretion, reduced pain, and promoted healing of lesions.

Initial Episodes of Herpes Genitalis

In placebo-controlled trials, 58 patients with initial genital herpes were treated with intravenous acyclovir 5 mg/kg or placebo (27 patients treated with acyclovir and 31 treated with placebo) every 8 hours for 5 days.  Acyclovir decreased the duration of viral excretion, new lesion formation, and duration of vesicles, and promoted healing of lesions.

Herpes Simplex Encephalitis

Sixty-two patients ages 6 months to 79 years with brain biopsy-proven herpes simplex encephalitis were randomized to receive either acyclovir (10 mg/kg every 8 hours) or vidarabine (15 mg/kg/day) for 10 days (28 were treated with acyclovir and 34 with vidarabine).  Overall mortality at 12 months for patients treated with acyclovir was 25% compared to 59% for patients treated with vidarabine.  The proportion of patients treated with acyclovir functioning normally or with only mild sequelae (e.g., decreased attention span) was 32% compared to 12% of patients treated with vidarabine.

Patients less than 30 years of age and those who had the least severe neurologic involvement at time of entry into study had the best outcome with treatment with acyclovir.  An additional controlled study performed in Europe demonstrated similar findings.

Neonatal Herpes Simplex Virus Infection

Two hundred and two infants with neonatal herpes simplex infections were randomized to receive either acyclovir 10 mg/kg every 8 hours (n=107) or vidarabine 30 mg/kg/day (n=95) for 10 days.  Outcomes are presented in Table 4.

 

               Table 4: Mortality at 1 Year

HSV Disease Classification	Treatment Group
	Acyclovir (n=107)	Vidarabine (n=95)
SEM* (n=85)	0/54	0/31
CNS† (n=71)	5/35	5/36
DISS‡ (n=46)	11/18	14/28

* SEM refers to localized infection with disease limited to skin, eye, and/or mouth.

† CNS refers to infection of the central nervous system with compatible neurologic and CSF findings.

‡ DISS refers to visceral organ involvement such as hepatitis or pneumonitis with or without CNS involvement.

 

Rates of neurologic sequelae at 1 year were comparable between the treatment groups.

Varicella-Zoster Infetions in Immunocompromised Patients

A multicenter trial of acyclovir at a dose of 500 mg/m2 every 8 hours for 7 days was conducted in immunocompromised patients with zoster infections (shingles).  Ninety-four (94) patients were evaluated (52 patients were treated with acyclovir and 42 with placebo).  Acyclovir was superior to placebo as measured by reductions in cutaneous dissemination and visceral dissemination.

Indications and Usage for Acyclovir Injection

Herpes Simplex Infections in Immunocompromised Patients

Acyclovir Sodium Injection is indicated for the treatment of initial and recurrent mucosal and cutaneous herpes simplex (HSV-1 and HSV-2) in immunocompromised patients.

Initial Episodes of Herpes Genitalis

Acyclovir Sodium Injection is indicated for the treatment of severe initial clinical episodes of herpes genitalis in immuno-competent patients.

Herpes Simplex Encephalitis

Acyclovir Sodium Injection is indicated for the treatment of herpes simplex encephalitis.

Neonatal Herpes Simplex Virus Infection

Acyclovir Sodium Injection is indicated for the treatment of neonatal herpes infections.

Varicella-Zoster Infections in Immunocompromised Patients

Acyclovir Sodium Injection is indicated for the treatment of varicella-zoster (shingles) infections in immunocompromised patients.

Contraindications

Acyclovir Sodium Injection is contraindicated for patients who develop hypersensitivity to acyclovir or valacyclovir.

Warnings

Acyclovir Sodium Injection is intended for intravenous infusion only, and should not be administered topically, intramuscularly, orally, subcutaneously, or in the eye.  Intravenous infusions must be given over a period of at least 1 hour to reduce the risk of renal tubular damage (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).

Renal failure, in some cases resulting in death, has been observed with acyclovir therapy (see ADVERSE REACTIONS: Observed During Clinical Practice and OVERDOSAGE).  Thrombotic thrombocytopenic purpura/ hemolytic uremic syndrome (TTP/HUS), which has resulted in death, has occurred in immunocompromised patients receiving acyclovir therapy.

Precautions

General

Precipitation of acyclovir crystals in renal tubules can occur if the maximum solubility of free acyclovir (2.5 mg/mL at 37°C in water) is exceeded or if the drug is administered by bolus injection.  Ensuing renal tubular damage can produce acute renal failure.

Abnormal renal function (decreased creatinine clearance) can occur as a result of acyclovir administration and depends on the state of the patient’s hydration, other treatments, and the rate of drug administration.  Concomitant use of other nephrotoxic drugs, pre-existing renal disease, and dehydration make further renal impairment with acyclovir more likely.

Administration of acyclovir by intravenous infusion must be accompanied by adequate hydration.

When dosage adjustments are required, they should be based on estimated creatinine clearance (see DOSAGE AND ADMINISTRATION).

Approximately 1% of patients receiving intravenous acyclovir have manifested encephalopathic changes characterized by either lethargy, obtundation, tremors, confusion, hallucinations, agitation, seizures, or coma.  Acyclovir should be used with caution in those patients who have underlying neurologic abnormalities and those with serious renal, hepatic, or electrolyte abnormalities, or significant hypoxia.

Drug Interactions

See CLINICAL PHARMACOLOGY: Pharmacokinetics.

Carcinogenesis, Mutagenesis, Impairment of Fertility

The data presented below include references to peak steady-state plasma acyclovir concentrations observed in humans treated with 30 mg/kg/day (10 mg/kg every 8 hours, dosing appropriate for treatment of herpes zoster or herpes encephalitis), or 15 mg/kg/day (5 mg/kg every 8 hours, dosing appropriate for treatment of primary genital herpes or herpes simplex infections in immunocompromised patients).  Plasma drug concentrations in animal studies are expressed as multiples of human exposure to acyclovir at the higher and lower dosing schedules (see CLINICAL PHARMACOLOGY: Pharmacokinetics).

Acyclovir was tested in lifetime bioassays in rats and mice at single daily doses of up to 450 mg/kg administered by gavage.  There was no statistically significant difference in the incidence of tumors between treated and control animals, nor did acyclovir shorten the latency of tumors.  At 450 mg/kg/day, plasma concentrations in both the mouse and rat bioassay were lower than concentrations in humans.

Acyclovir was tested in 16 in vitro and in vivo genetic toxicity assays.  Acyclovir was positive in 5 of the assays.

Acyclovir did not impair fertility or reproduction in mice (450 mg/kg/day, PO) or in rats (25 mg/kg/day, SC).  In the mouse study, plasma levels were the same as human levels, while in the rat study, they were 1 to 2 times human levels.  At higher doses (50 mg/kg/day, SC) in rats and rabbits (1 to 2 and 1 to 3 times human levels, respectively) implantation efficacy, but not litter size, was decreased.  In a rat peri- and post-natal study at 50 mg/kg/day, SC, there was a statistically significant decrease in group mean numbers of corpora lutea, total implantation sites, and live fetuses.

No testicular abnormalities were seen in dogs given 50 mg/kg/day, IV for 1 month (1 to 3 times human levels) or in dogs given 60 mg/kg/day orally for 1 year (the same as human levels).  Testicular atrophy and aspermatogenesis were observed in rats and dogs at higher dose levels.

Pregnancy: Teratogenic Effects

Pregnancy Category B.

Acyclovir administered during organogenesis was not teratogenic in the mouse (450 mg/kg/day, PO), rabbit (50 mg/kg/day, SC and IV) or rat (50 mg/kg/day, SC).  These exposures resulted in plasma levels the same as, 4 and 9, and 1 and 2 times, respectively, human levels.

There are no adequate and well-controlled studies in pregnant women.  A prospective epidemiologic registry of acyclovir use during pregnancy was established in 1984 and completed in April 1999.  There were 749 pregnancies followed in women exposed to systemic acyclovir during the first trimester of pregnancy resulting in 756 outcomes.  The occurrence rate of birth defects approximates that found in the general population.  However, the small size of the registry is insufficient to evaluate the risk for less common defects or to permit reliable or definitive conclusions regarding the safety of acyclovir in pregnant women and their developing fetuses.  Acyclovir should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

Acyclovir concentrations have been documented in breast milk in two women following oral administration of acyclovir and ranged from 0.6 to 4.1 times corresponding plasma levels.  These concentrations would potentially expose the nursing infant to a dose of acyclovir up to 0.3 mg/kg/day.  Acyclovir should be administered to a nursing mother with caution and only when indicated.

Pediatric Use

See DOSAGE AND ADMINISTRATION.

Geriatric Use

Clinical studies of acyclovir did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger patients.  Other reported clinical experience has identified differences in the severity of CNS adverse events between elderly and younger patients (see ADVERSE REACTIONS: Observed During Clinical Practice).  In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased renal function, and of concomitant disease or other drug therapy.  This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function.  Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Adverse Reactions

The adverse reactions listed below have been observed in controlled and uncontrolled clinical trials in approximately 700 patients who received acyclovir at approximately 5 mg/kg (250 mg/m2) 3 times daily, and approximately 300 patients who received approximately 10 mg/kg (500 mg/m2) 3 times daily.

The most frequent adverse reactions reported during administration of acyclovir were inflammation or phlebitis at the injection site in approximately 9% of the patients, and transient elevations of serum creatinine or BUN in 5% to 10% (the higher incidence occurred usually following rapid [less than 10 minutes] intravenous infusion).  Nausea and/or vomiting occurred in approximately 7% of the patients (the majority occurring in nonhospitalized patients who received 10 mg/kg).  Itching, rash, or hives occurred in approximately 2% of patients.  Elevation of transaminases occurred in 1% to 2% of patients.

The following hematologic abnormalities occurred at a frequency of less than 1%: anemia, neutropenia, thrombocytopenia, thrombocytosis, leukocytosis, and neutrophilia.  In addition, anorexia and hematuria were observed.

Observed During Clinical Practice

In addition to adverse events reported from clinical trials, the following events have been identified during post-approval use of Acyclovir Sodium Injection in clinical practice.  Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made.  These events have been chosen for inclusion due to either their seriousness, frequency of reporting, potential causal connection to acyclovir, or a combination of these factors.

General:  Anaphylaxis, angioedema, fatigue, fever, headache, pain, peripheral edema.

Digestive:  Abdominal pain, diarrhea, gastrointestinal distress, nausea.

Cardiovascular:  Hypotension.

Hematologic and Lymphatic:  Disseminated intravascular coagulation, hemolysis,leukocytoclastic vasculitis, leukopenia, lymphadenopathy.

Hepatobiliary Tract and Pancreas:  Elevated liver function tests, hepatitis, hyperbilirubinemia,jaundice.

Musculoskeletal:  Myalgia.

Nervous:  Aggressive behavior, agitation, ataxia, coma, confusion, delirium, dizziness, dysathria, encephalopathy, hallucinations, obtundation, paresthesia, psychosis, seizure, somnolence, tremor.  These symptoms may be marked, particularly in older adults (see PRECAUTIONS).

Skin:  Alopecia, erythema multiforme, photosensitive rash, pruritus, rash, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria.  Severe local inflammatory reactions, including tissue necrosis, have occurred following infusion of acyclovir into extravascular tissues.

Special Senses:  Visual abnormalities.

Urogenital:  Renal failure, elevated blood urea nitrogen, elevated creatinine (see WARNINGS).

Overdosage

Overdoses involving ingestions of up to 20 g have been reported.  Adverse events that have been reported in association with overdosage include agitation, coma, seizures, and lethargy.  Precipitation of acyclovir in renal tubules may occur when the solubility (2.5 mg/mL) is exceeded in the intratubular fluid.  Overdosage has been reported following bolus injections or inappropriately high doses, and in patients whose fluid and electrolyte balance were not properly monitored.  This has resulted in elevated BUN and serum creatinine, and subsequent renal failure.  In the event of acute renal failure and anuria, the patient may benefit from hemodialysis until renal function is restored (see DOSAGE AND ADMINISTRATION).

Acyclovir Injection Dosage and Administration

CAUTION - RAPID OR BOLUS INTRAVENOUS INJECTION MUST BE AVOIDED (see WARNINGS and PRECAUTIONS).

INTRAMUSCULAR OR SUBCUTANEOUS INJECTION MUST BE AVOIDED (see WARNINGS).

Therapy should be initiated as early as possible following onset of signs and symptoms of herpes infections. 

A maximum dose equivalent to 20 mg/kg every 8 hours should not be exceeded for any patient.

Dosage

HERPES SIMPLEX INFECTIONS

MUCOSAL AND CUTANEOUS HERPES SIMPLEX (HSV-1 and HSV-2)

INFECTIONS IN IMMUNOCOMPROMISED PATIENTS:

Adults and Adolescents (12 years of age and older):

5 mg/kg infused at a constant rate over 1 hour, every 8 hours for 7 days.

 

Pediatrics (Under 12 years of age):

10 mg/kg infused at a constant rate over 1 hour, every 8 hours for 7 days.

 

SEVERE INITIAL CLINICAL EPISODES OF HERPES GENITALIS:

Adults and Adolescents (12 years of age and older):

5 mg/kg infused at a constant rate over 1 hour, every 8 hours for 5 days.

 

HERPES SIMPLEX ENCEPHALITIS:

Adults and Adolescents (12 years of age and older): 

10 mg/kg infused at a constant rate over 1 hour, every 8 hours for 10 days.

 

Pediatrics (3 months to 12 years of age):

20 mg/kg infused at a constant rate over 1 hour, every 8 hours for 10 days.

 

Neonatal Herpes Simplex Virus Infections (Birth to 3 months):

10 mg/kg infused at a constant rate over 1 hour, every 8 hours for 10 days.  In neonatal herpes simplex infections, doses of 15 mg/kg or 20 mg/kg (infused at a constant rate over 1 hour every 8 hours) have been used; the safety and efficacy of these doses are not known.

VARICELLA-ZOSTER INFECTIONS

ZOSTER IN IMMUNO­COMPROMISED PATIENTS:

Adults and Adolescents (12 years of age and older: 

10 mg/kg infused at a constant rate over 1 hour, every 8 hours for 7 days.

 

Pediatrics (Under 12 years of age):

20 mg/kg infused at a constant rate over 1 hour, every 8 hours for 7 days.

Obese Patients

Obese patients should be dosed at the recommended adult dose using Ideal Body Weight.

PATIENTS WITH ACUTE OR CHRONIC RENAL IMPAIRMENT: Refer to DOSAGE AND ADMINISTRATION section for recommended doses, and adjust the dosing interval as indicated in Table 5.

Table 5: Dosage Adjustments for Patients with Renal Impairment

Creatinine Clearance (mL/min/1.73 m2)	Percent of Recommended Dose	Dosing Interval (hours)
>50 25-50 10-25 0-10	100% 100% 100% 50%	8 12 24 24

Hemodialysis

For patients who require dialysis, the mean plasma half-life of acyclovir during hemodialysis is approximately 5 hours.  This results in a 60% decrease in plasma concentrations following a six-hour dialysis period.  Therefore, the patient’s dosing schedule should be adjusted so that an additional dose is administered after each dialysis.

Peritoneal Dialysis

No supplemental dose appears to be necessary after adjustment of the dosing interval.

Administration

The calculated dose should be further diluted in an appropriate intravenous solution at a volume selected for administration during each 1 hour infusion.  Infusion concentrations of approximately 7 mg/mL or lower are recommended.  In clinical studies, the average 70 kg adult received between 60 and 150 mL of fluid per dose.  Higher concentrations (e.g., 10 mg/mL) may produce phlebitis or inflammation at the injection site upon inadvertent extravasation.  Standard, commercially available electrolyte and glucose solutions are suitable for intravenous administration; biologic or colloidal fluids (e.g., blood products, protein solutions, etc.) are not recommended.

Once diluted for administration, each dose should be used within 24 hours.

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

How is Acyclovir Injection Supplied

Acyclovir Sodium Injection is available as:

Product No.	NDC No.
302510	63323-325-10	Acyclovir Sodium Injection equivalent to acyclovir, 50 mg/mL in a 10 mL plastic vial, in packages of 10.
302520	63323-325-20	Acyclovir Sodium Injection equivalent to acyclovir, 50 mg/mL in a 20 mL plastic vial, in packages of 10.

Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

Discard unused portion.

Vial stoppers do not contain natural rubber latex.

45769G

Revised: March 2008

PACKAGE LABEL - PRINCIPAL DISPLAY - Acyclovir 10 mL Single Dose Vial Label

NDC 63323-325-10

302510

Acyclovir Sodium Injection

500 mg/10 mL*

(50 mg/mL)

For IV Infusion Only

Must Be Diluted Prior To Use

Rx only

10 mL Single Dose Vial

 

PACKAGE LABEL - PRINCIPAL DISPLAY - Acyclovir 10 mL Single Dose Vial Tray Label

NDC 63323-325-10

302510

Acyclovir Sodium Injection

500 mg/10 mL*

(50 mg/mL)

For IV Infusion Only

Must Be Diluted Prior To Use

10 mL Single Dose Vial

10 Vials

Rx only

 

ACYCLOVIR  acyclovir sodium  injection, powder, for solution

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 63323-325 Route of Administration INTRAVENOUS DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength ACYCLOVIR SODIUM (ACYCLOVIR) ACYCLOVIR 50 mg  in 1 mL

Inactive Ingredients Ingredient Name Strength No Inactive Ingredients Found

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 63323-325-10 10 VIAL In 1 TRAY contains a VIAL, SINGLE-DOSE 1 10 mL In 1 VIAL, SINGLE-DOSE This package is contained within the TRAY (63323-325-10) 2 63323-325-20 10 VIAL In 1 TRAY contains a VIAL, SINGLE-DOSE 2 20 mL In 1 VIAL, SINGLE-DOSE This package is contained within the TRAY (63323-325-20)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA074930	10/17/2000

Labeler - APP Pharmaceuticals, LLC (608775388)

Establishment
Name	Address	ID/FEI	Operations
APP Pharmaceuticals, LLC		840771732	MANUFACTURE

Revised: 01/2012APP Pharmaceuticals, LLC

Privine Drops

Pronunciation: naf-AZ-oh-leen
Generic Name: Naphazoline
Brand Name: Privine

Privine Drops are used for:

Temporarily relieving stuffy nose due to cold, hay fever, or other upper respiratory allergies associated with sinus inflammation. It may also be used for other conditions as determined by your doctor.

Privine Drops are a decongestant nose drop. It works by shrinking swollen and congested nasal tissues, relieving congestion and improving drainage and breathing through the nose.

Do NOT use Privine Drops if:

• you are allergic to any ingredient in Privine Drops


• you have narrow-angle glaucoma


• you are taking furazolidone or have taken a monoamine oxidase (MAO) inhibitor (eg, phenelzine) within the last 14 days

Contact your doctor or health care provider right away if any of these apply to you.

Before using Privine Drops:

Some medical conditions may interact with Privine Drops. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

• if you are pregnant, planning to become pregnant, or are breast-feeding


• if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement


• if you have allergies to medicines, foods, or other substances


• if you have heart disease, diabetes, high blood pressure, or an overactive thyroid

Some MEDICINES MAY INTERACT with Privine Drops. Tell your health care provider if you are taking any other medicines, especially any of the following:

• Furazolidone, MAO inhibitors (eg, phenelzine), or tricyclic antidepressants (eg, amitriptyline) because side effects, such as headache, increased body temperature, and high blood pressure, may be increased


• Bromocriptine or cocaine because the actions and side effects of these medicines may be increased

This may not be a complete list of all interactions that may occur. Ask your health care provider if Privine Drops may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Privine Drops:

Use Privine Drops as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• To use nose drops, gently blow your nose. Lie down and tilt your head back. Breathe through your mouth. Insert the dropper tip in the nose no more than one-third inch. Try not to touch the dropper tip to the inside of your nose. Place the correct number of drops in your nose. Continue to lie down with your head tilted back for 2 minutes.


• If you miss a dose of Privine Drops and are using it regularly, use it as soon as possible. If it is much more than an hour since your missed dose, skip the missed dose and go back to your regular dosing schedule. Do not use 2 doses at once.

Ask your health care provider any questions you may have about how to use Privine Drops.

Important safety information:

• Privine Drops are for use in the nose only. Avoid contact with the eyes or mouth.


• Do not share Privine Drops with anyone else. Sharing may cause an infection to spread to another person.


• Diabetes patients - Privine Drops may affect your blood sugar. Check blood sugar levels closely and ask your doctor before adjusting the dose of your diabetes medicine.


• Privine Drops are not recommended for use in CHILDREN younger than 6 years of age. Safety and effectiveness in this age group have not been confirmed.


• PREGNANCY and BREAST-FEEDING: If you become pregnant, discuss with your doctor the benefits and risks of using Privine Drops during pregnancy. It is unknown if Privine Drops are excreted in breast milk. If you are or will be breast-feeding while you are using Privine Drops, check with your doctor or pharmacist to discuss the risks to your baby.

Possible side effects of Privine Drops:

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Burning; increased nasal discharge; sneezing; stinging.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue).

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

See also: Privine side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Privine Drops may be harmful if swallowed.

Proper storage of Privine Drops:

Store Privine Drops at room temperature, between 68 and 77 degrees F (20 and 25 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Keep Privine Drops out of the reach of children and away from pets.

General information:

• If you have any questions about Privine Drops, please talk with your doctor, pharmacist, or other health care provider.


• Privine Drops are to be used only by the patient for whom it is prescribed. Do not share it with other people.


• If your symptoms do not improve or if they become worse, check with your doctor.


• Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Privine Drops. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More Privine resources

• Privine Side Effects (in more detail)
• Privine Use in Pregnancy & Breastfeeding
• Privine Drug Interactions
• Privine Support Group
• 2 Reviews for Privine - Add your own review/rating

Compare Privine with other medications

• Nasal Congestion

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(Nicotine)

Read all of this leaflet carefully because it contains important information for you.

This medicine is available without prescription to help relieve and/or prevent cravings for nicotine when you are trying to give up smoking or for when you can’t or don’t want to smoke cigarettes. However, you need to use it carefully to get the best results from it.

• Keep this leaflet, you may need to read it again


• Ask your pharmacist if you need more information or advice

What this medicine is for

This medicine contains nicotine which belongs to a group of medicines called nicotine replacement therapy (NRT). It acts to substitute the nicotine that you normally get from cigarettes and can be used to relieve and/or prevent cravings for nicotine when you are stopping smoking, cutting down or when you can’t or don’t want to smoke cigarettes.

It can be used to relieve the symptoms of nicotine withdrawal and to relieve and/or prevent the cravings for nicotine that you get:

• When you stop smoking completely


• When you cut down on the number of cigarettes you smoke while you try to give up


• If you feel unable to stop smoking but you don’t want to smoke cigarettes or you want to avoid causing harm to others, such as when you are with friends or family, or


• If you feel unable to stop smoking completely but you can’t smoke cigarettes, such as when you are at a party, in the pub, at work, on a plane or train etc.

When you stop smoking, cut down, or you can’t or don’t want to smoke cigarettes, your body misses the nicotine that you have been getting from the smoke. You may experience unpleasant feelings and a strong desire to smoke (“craving”).

This shows that you are dependent on nicotine. When you use the inhalator, nicotine is released and passes into your body through the lining of your mouth. The nicotine is sufficient to relieve and/or prevent the unpleasant withdrawal symptoms. It will also help to relieve and/or prevent your craving to smoke but will not give you the “buzz” you get from a cigarette.

You should always aim to stop smoking completely whilst using the inhalator. To help you cut down or stop smoking completely you should also try to use a behavioural support programme to increase your chances of successfully stopping smoking.

Benefits you can get from using NRT instead of smoking

For the best effect, ensure that you use Boots NicAssist Inhalator correctly – see “How to use the inhalator”.

The benefits of stopping smoking far outweigh any potential risk from using nicotine from NRT. It is the toxins in cigarette smoke such as tar, lead, cyanide and ammonia that cause smoking related disease and death, not the nicotine.

• 
  You may think that smoking helps relieve feelings of anxiety and stress, but it does not deal with the cause of the stress and leads to a number of serious diseases. In addition, the feeling of relaxation after smoking is temporary, with withdrawal symptoms and cravings soon returning
  
  
  Nicotine replacement therapy can help relieve nicotine withdrawal symptoms such as irritability, low mood, anxiety, restlessness and cravings when used in place of cigarettes.


• 
  NRT may benefit smokers who want to quit, by helping to control weight gain that may be experienced when trying to stop smoking
  
  
  Use of NRT is safer than smoking tobacco but as soon as you are ready, you should aim to stop smoking completely.

Before you use this medicine

This medicine can be used by adults and children of 12 years and over. However, some people should not use this medicine or should seek the advice of their pharmacist or doctor first.

Do not use:

• 
  If you are allergic to any of the ingredients in this medicine (see “What is in this medicine”)


• 
  If you are a child under 12 years of age
  

Talk to your pharmacist, nurse or doctor:

• If you are in hospital because of heart disease (e.g. heart attack, problems with your heart rate or rhythm, stroke) – try to give up smoking first without using NRT. However, once you are out of hospital, if you still need help to stop smoking, you can use this medicine. For other heart conditions that do not require you to be in hospital, using NRT is better than continuing to smoke


• If you have diabetes – monitor your blood sugar levels more often when you start using this medicine. You may find that you need to adjust the amount of insulin you use, or the amount of tablets you take (ask your doctor or diabetes nurse about this)


• If you have an ulcer in your stomach or upper intestine or problems such as pain or swelling of the stomach or oesophagus (the passage between your mouth and stomach)


• If your liver or kidneys do not work properly


• If you have an overactive thyroid gland


• If you have high blood pressure due to a tumour near your kidney (your doctor may have told you that you have a condition called phaeochromocytoma)


• If you are taking other medicines regularly prescribed by your doctor (see “If you take other medicines”)


• If you have long term throat problems or difficulty breathing due to bronchitis (a condition which produces lots of phlegm on the chest), emphysema or asthma – the inhalator may not be suitable for you to use and you may be advised to use a different type of NRT (ask your pharmacist about other NRT products such as patches, gums, lozenges, microtabs)


• If you are pregnant or breastfeeding (see “Other important information”)

Choking risk: This product contains small cartridges, which could be a choking hazard if a child attempts to swallow one. Keep any unused cartridges in the pack out of the sight and reach of children.

Other important information

If you are pregnant: You should try to stop smoking without using NRT.

However, if you still need help to stop smoking, you can use this product as the risk to your baby is far less than if you continue to smoke. You should talk to your pharmacist, nurse or doctor for more advice.

NRT products that are used intermittently, such as this one, may be preferable to nicotine patches. However if you feel sick or are sick (morning sickness) the patches may be better for you. If you do use nicotine patches they should be taken off before bedtime.

If you are breastfeeding: You should try to stop smoking without using NRT.

However, if you still need help to stop smoking, you should use NRT products that are used intermittently, not patches. You should talk to your pharmacist, nurse or doctor for more advice.

Breastfeeding your baby just before you use the inhalator makes sure that your baby gets the smallest amount of nicotine possible.

The amount of nicotine that your baby may receive when you are using the inhalator or other NRT products is much smaller and less harmful than the second-hand smoke they would inhale if you smoked. Tobacco smoke causes breathing and other health problems in babies and children. If your husband, partner or other family members smoke too, try to get them to give up with you.

Nicotine products and children: Nicotine can be very dangerous to children. The amount of nicotine tolerated by adults and adolescents can make children very ill, and can sometimes be fatal. Do not leave your inhalator or cartridges where children may get hold of them.

If you take other medicines

Before you use this medicine, make sure that you tell your pharmacist about ANY other medicines you might be using at the same time, particularly the following:

• Theophylline, clozapine, ropinirole – your doctor may want to monitor the amount of medicine that you take

When you stop smoking or reduce the amount of cigarettes you smoke, your metabolism slows down. This can mean that some medicines may stay in your body longer than usual.

If you take any medicine on a regular basis, tell your doctor that you intend to stop smoking or reduce the amount of cigarettes you smoke and follow his or her advice about these other medicines.

How and when to use this medicine

Check the foil is not broken before use. If it is, do not use that cartridge.

When to use the inhalator

Read all of the following information carefully before using the inhalator:

• Read the following instructions which explain when you should use the inhalator and the maximum amount of inhalator cartridges you should be using each day


• Read the “How to use the inhalator” instructions to make sure that you use the inhalator correctly to ensure that nicotine is released and passes into your body through the lining of your mouth
  
  
  The number of inhalator cartridges you use each day will depend on how many cigarettes you smoke and how strong they are.


• Boots NicAssist 10 mg Inhalator should be used whenever the urge to smoke is felt or when you would normally expect to have cravings to smoke


• It is recommended that to successfully reduce the amount of cigarettes you smoke or stop smoking completely you should use the inhalator as much as possible and it is up to you how many inhalations (puffs) you take, how often you take them and for how long


• 
  If you are ready to stop smoking completely, you should use the inhalator, when needed, to replace all of your cigarettes. As soon as you feel ready (this could be after a number of weeks or months) you should reduce the number of cartridges used per day until you no longer need to use the inhalator


• 
  If you are not yet ready to stop smoking completely, you should replace as many cigarettes as possible with the inhalator. Boots NicAssist 10 mg Inhalator provides a safer alternative to smoking for you and those around you, as it is the toxins in cigarette smoke that cause harm, not the nicotine. Reducing the amount of cigarettes you smoke may also help you to become more motivated to stop smoking. As soon as you feel ready, you should aim to stop smoking completely


• 
  You can also use the inhalator when you can’t or don’t want to smoke, such as social occasions e.g. at a party, in the pub, or for when you are at work, or on a plane or train etc. When making an attempt to stop smoking completely behavioural therapy, advice and support will normally improve the success rate.

Adults and children of 12 years and over:

Use the inhalator when required, up to a maximum of 12 cartridges per day.

Don’t use more than 12 cartridges per day.

You should always aim to stop smoking completely whilst using the inhalator.

If you are unable to reduce your use of the inhalator you should ask for help and advice from a pharmacist, nurse or doctor.

Do not give this medicine to children under 12 years of age.

How to use the inhalator

Please read the following information.

Setting up the inhalator

1. Take the sealed plastic tray from the box. Peel back the foil.

2. Take the plastic mouthpiece from the tray.

3. Twist the two sections of the mouthpiece until the two marks line up. Then pull the mouthpiece apart.

4. Take a cartridge from the tray. Push the cartridge firmly into the bottom of the mouthpiece until the seal breaks.

5. Put the top section on the mouthpiece, lining up the two marks. Push together firmly to break the cartridge seal.

6. Twist to lock.

Special information about using the inhalator

Using the inhalator

1. To use the inhalator, take either deep or shallow puffs. Choose the way that suits you. Either way, your body will receive the amount of nicotine required to relieve and/or prevent cravings.

You may find it takes more effort than inhaling from a cigarette, but the amount of nicotine you get through the lining of your mouth is the same whether you take deep or shallow puffs.

2. The amount of nicotine that you may get from one puff from the inhalator is less than that you may get from a cigarette and you may need to take more puffs from the inhalator.

It is up to you how many inhalations (puffs) you take, how often you take them and for how long.

3. Each cartridge will provide you with about 20 minutes worth of puffs. You can divide this time how you like. For example, you could use a cartridge for four 5 minute inhalation periods. Or you could use a cartridge for 10 minutes on waking and then for two periods of 5 minutes later on in the day.

Once the cartridge is used up, normally after a total of 20 minutes of use, you will need to change it.

Changing a cartridge

1. Open the mouthpiece as in step 3 of “Setting up the inhalator”. Pull out the cartridge and dispose of it safely (see “How to clean, store and dispose of this medicine”)

2. Put a new cartridge into the inhalator as in steps 4 to 6 of “Setting up the inhalator”.

Effect of temperature on the inhalator

The inhalator works best at room temperature and it is best not to use the inhalator in the cold.

In cold surroundings (below 15ºC or 59ºF) you may have to inhale more often to get the same amount of nicotine as when using the inhalator at room temperature.

When you are in surroundings above 30ºC or 86ºF, you should inhale less often to avoid taking in too much nicotine.

If you have used the inhalator too often or too much: You may get the following symptoms – feeling sick, salivation, pain in your stomach, diarrhoea, sweating, headache, dizziness, hearing disturbance, weakness. If this happens stop using the inhalator and do not smoke. Contact a doctor or hospital casualty department straight away. Take the medicine and this leaflet with you.

If a child under 12 accidentally uses, swallows, sucks or chews some of this medicine take them to casualty immediately. Take the medicine and this leaflet with you. Nicotine ingestion by a child may cause severe poisoning.

Possible side effects

Most people can use this medicine without any problems but sometimes you may notice some side effects. Many of these effects are due to nicotine, they may also happen when you smoke.

If you notice any of the following serious side effects, stop using the medicine, do not smoke and see your doctor as soon as possible:

• You develop a fast, slow or irregular heart beat


• You have an allergic reaction to the inhalator such as rash, itching or swelling of the tongue, mouth or throat (go straight to casualty if severe)

Effects related to stopping smoking (nicotine withdrawal)

You may experience unwanted effects because by stopping smoking or using the inhalator when you are unable to smoke you have reduced the amount of nicotine you are taking. You may also experience these effects if you use too few inhalator cartridges or puffs from the inhalator before you are ready to reduce your nicotine intake.

These effects include:

• Irritability or aggression


• Feeling low


• Anxiety


• Restlessness


• Poor concentration


• Increased appetite or weight gain


• Urges to smoke (craving)


• Night time awakening or sleep disturbance


• Lowering of heart rate

Effects of too much nicotine

It is possible to inhale too much nicotine if you use the inhalator in very warm surroundings (see “Effect of temperature on the inhalator”). You may also get these effects if you are not used to inhaling tobacco as you smoke. You may be able to relieve these effects by using the inhalator less often.

These effects include:

• Feeling faint


• Feeling sick (nausea)


• Headache

Side effects of the inhalator

When you first start using the inhalator you may be more likely to notice some of these side effects.

Very common side effects:

(more than 1 in every 10 people are affected)

• Headache


• Cough


• Irritation of the mouth or throat

Common side effects:

(less than 1 in every 10 people are affected)

• Dizziness


• Stomach discomfort


• Hiccups


• Feeling sick (nausea)


• Being sick (vomiting)


• Blocked nose

Uncommon side effects:

(less than 1 in every 100 people are affected)

• Chest palpitations

Very rare side effects:

(less than 1 in 10,000 people are affected)

• Abnormal beating of the heart

If any of the side effects get serious, or you notice any side effect not listed here, please tell your pharmacist or doctor.

When you stop smoking you may also develop mouth ulcers. The reason why this happens is unknown.

How to clean, store and dispose of this medicine

Cleaning the inhalator

Clean the empty mouthpiece several times a week by rinsing it in water.

Storing the inhalator and cartridges

Store below 30ºC.

Keep this medicine in a safe place out of the sight and reach of children and animals, preferably in a locked cupboard. Nicotine in high amounts can be very dangerous and sometimes fatal if used or swallowed by small children.

Use by the date on the foil or the end flap of the carton. After this date return any unused medicine to your nearest pharmacy for safe disposal.

Dispose of any used inhaler cartridges safely.

When a cartridge is used up, it is very important that you dispose of the empty cartridge carefully as it still contains some nicotine fixed to the plug. This nicotine is not available for inhalation but could be harmful to children or pets if swallowed or sucked.

You can return the empty cartridge to the foil tray then dispose of all the empty cartridges with your household rubbish.

What is in this medicine

Each inhalation cartridge contains Nicotine 10mg, which is the active ingredient.

As well as the active ingredient, the inhalation cartridges also contain menthol.

Boots NicAssist 10 mg Inhalator consists of a plastic mouthpiece into which you insert a tube-like cartridge containing 10 mg of nicotine, the active ingredient, held in a porous plug.

The plug also contains menthol to give the nicotine a slight minty flavour.

Boots NicAssist 10 mg Inhalator is supplied as either a starter or a refill pack.

The starter pack contains a plastic tray sealed with foil containing 6 cartridges and a plastic mouthpiece.

The refill pack contains a mouthpiece and 42 cartridges.

Who makes this medicine

This product is manufactured for

The Boots Company PLC

Nottingham

NG2 3AA

by

McNeil AB

Helsingborg

Sweden

The Marketing Authorisation holder is

McNeil Products Ltd

Maidenhead

Berkshire

SL6 3UG

Leaflet prepared June 2010.

If you would like any further information about this product, please contact

The Boots Company PLC

Nottingham

NG2 3AA

Other formats

To request a copy of this leaflet in Braille, large print or audio please call, free of charge:

0800 198 5000 (UK only)

Please be ready to give the following information:

Product name: Boots NicAssist 10 mg Inhalator

Reference Number: 15513/0179

This is a service provided by the Royal National Institute of Blind People.

Merbentyl Syrup

1. Name Of The Medicinal Product

Merbentyl Syrup

2. Qualitative And Quantitative Composition

Dicycloverine Hydrochloride 10mg

3. Pharmaceutical Form

Syrup

4. Clinical Particulars

4.1 Therapeutic Indications

Merbentyl is a smooth muscle antispasmodic primarily indicated for treatment of functional conditions involving smooth muscle spasm of the gastrointestinal tract. The commonest of these are irritable colon (mucous colitis, spastic colon).

4.2 Posology And Method Of Administration

Adults

One to two 5ml spoonfuls (10 - 20mg) three times daily before or after meals.

Children (2-12 years):

One 5ml spoonful (10mg) three times daily.

Children (6 months - 2 years)

5 - 10mg three or four times daily, 15 minutes before feeds. Do not exceed a daily dose of 40mg. If it is necessary to dilute Merbentyl Syrup this may be done using Syrup or if diluted immediately prior to use with water.

4.3 Contraindications

Known idiosyncrasy to dicycloverine hydrochloride. Infants under 6 months of age.

Patients with rare hereditary problems of fructose intolerance, glucose galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

4.4 Special Warnings And Precautions For Use

Products containing dicycloverine hydrochloride should be used with caution in any patient with or suspected of having glaucoma or prostatic hypertrophy. Use with care in patients with hiatus hernia associated with reflux oesophagitis because anticholinergic drugs may aggravate the condition. There are reports of infants, 3 months of age and under, administered dicycloverine hydrochloride syrup who have evidenced respiratory symptoms (breathing difficulty, shortness of breath, breathlessness, respiratory collapse, apnoea) as well as seizures, syncope, asphyxia, pulse rate fluctuations, muscular hypotonia and coma. The above symptoms have occurred within minutes of ingestion and lasted 20-30 minutes. The symptoms were reported in association with dicycloverine hydrochloride syrup therapy but the cause and effect relationship has neither been disproved or proved. The timing and nature of the reactions suggest that they were a consequence of local irritation and/or aspiration, rather than to a direct pharmacological effect. Although no causal relationship between these effects, observed in infants and dicycloverine administration has been established, dicycloverine hydrochloride is contra-indicated in infants under 6 months of age.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

None stated.

4.6 Pregnancy And Lactation

Epidemiological studies in pregnant women with products containing dicycloverine hydrochloride (at doses up to 40mg/day) have not shown that dicycloverine hydrochloride increases the risk of foetal abnormalities if administered during the first trimester of pregnancy. Reproduction studies have been performed in rats and rabbits at doses of up to 100 times the maximum recommended dose (based on 60mg per day for an adult person) and have revealed no evidence of impaired fertility or harm to the foetus due to dicycloverine. Since the risk of teratogenicity cannot be excluded with absolute certainty for any product, the drug should be used during pregnancy only if clearly needed.

It is not known whether dicycloverine is secreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when dicycloverine is administered to a nursing mother.

4.7 Effects On Ability To Drive And Use Machines

None stated.

4.8 Undesirable Effects

Side-effects seldom occur with Merbentyl. However, in susceptible individuals, dry mouth, thirst and dizziness may occur. On rare occasions, fatigue, sedation, blurred vision, rash, constipation, anorexia, nausea and vomiting, headache and dysuria have also been reported.

4.9 Overdose

Symptoms of Merbentyl overdosage are headache, dizziness, nausea, dry mouth, difficulty in swallowing, dilated pupils and hot dry skin. Treatment may include emetics, gastric lavage and symptomatic therapy if indicated.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Dicycloverine hydrochloride relieves smooth muscle spasm of the gastrointestinal tract.

Animal studies indicate that this action is achieved via a dual mechanism;

(1) a specific anticholinergic effect (antimuscarinic at the ACh-receptor sites) and

(2) a direct effect upon smooth muscle (musculotropic).

5.2 Pharmacokinetic Properties

After a single oral 20mg dose of dicycloverine hydrochloride in volunteers, peak plasma concentration reached a mean value of 58ng/ml in 1 to 1.5 hours. ¹⁴C labelled studies demonstrated comparable bioavailability from oral and intravenous administration. The principal route of elimination is via the urine.

5.3 Preclinical Safety Data

None stated.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Invert Syrup Medium

Citric Acid Monohydrate

Sodium Benzoate

Raspberry Flavour

Wild Cherry Bark Flavour

Blackcurrant Essence

Vanilla Essence

Purified water

6.2 Incompatibilities

None stated.

6.3 Shelf Life

3 years.

6.4 Special Precautions For Storage

Do not store above 25'C. Should be stored and dispensed in amber glass bottles.

6.5 Nature And Contents Of Container

Type III, EP amber glass bottles sealed with a polyethylene screw cap equiped with a polyethylene seal and pilferproof closure.

Pack size: 1 bottle containing 120ml syrup.

6.6 Special Precautions For Disposal And Other Handling

None stated.

7. Marketing Authorisation Holder

Sanofi-aventis

One Onslow Street

Guildford

Surrey, GU1 4YS, UK

8. Marketing Authorisation Number(S)

PL 04425/0047

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation: 13^th July 1983

Date of renewal: 31 July 2001

10. Date Of Revision Of The Text

December 2006

Legal category: POM