Vinorelbine

Dosage Form: injection
Vinorelbine

Tartrate

Injection

Package Insert

Rx ONLY

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 ≥1000 cells/mm3 prior to the administration of Vinorelbine. 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 Vinorelbine tartrate is injected. Administration of Vinorelbine tartrate injection may result in extravasation causing local tissue necrosis and/or thrombophlebitis. (SeeDOSAGE AND ADMINISTRATION: Administration Precautions.)

Vinorelbine Description

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) Vinorelbine 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 >1000 mg/mL in distilled water. The pH of Vinorelbine Tartrate Injection is approximately 3.5.

Vinorelbine - 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/h per 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 1169 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. (SeePRECAUTIONS.) 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. (SeeDOSAGE 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 Vinorelbine tartrate injection. (SeePRECAUTIONS: Drug Interactions.)

Clinical Trials

Data from 1 randomized clinical study (211 evaluable patients) with single-agent Vinorelbine and 2 randomized clinical trials (1044 patients) using Vinorelbine combined with cisplatin support the use of Vinorelbine tartrate injection in patients with advanced nonsmall cell lung cancer (NSCLC).

Single-Agent Vinorelbine

Single-agent Vinorelbine 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 Vinorelbine (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 Vinorelbine (143) or 5-FU/LV (68). Vinorelbine 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 Vinorelbine versus 5-FU/LV, respectively (P = 0.06). The 1-year survival rates were 24% (±4% SE) for Vinorelbine 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 Vinorelbine and 5-FU/LV were 12% and 3%, respectively.

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

A Phase III open-label, randomized study was conducted which compared Vinorelbine (25 mg/m2 per 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 Vinorelbine 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 Vinorelbine plus cisplatin was significantly better compared to the patients who received single-agent cisplatin. The results of this trial are summarized inTable 1.

Vinorelbine plus Cisplatin versus Vindesine plus Cisplatin versus Single-Agent Vinorelbine

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 Vinorelbine (30 mg/m2 per week), Vinorelbine (30 mg/m2 per week) plus cisplatin (120 mg/m2 days 1 and 29, then every 6 weeks), and vindesine (3 mg/m2 per 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 inTable 1. Survival was longer in patients treated with Vinorelbine plus cisplatin compared to those treated with vindesine plus cisplatin (Figure 2). Study results are summarized inTable 1.

Dose-Ranging Study

A dose-ranging study of Vinorelbine (20, 25, or 30 mg/m2 per 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 Vinorelbine Tartrate in Combination with Cisplatin in NSCLC

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

Indications and Usage for Vinorelbine

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

Contraindications

Administration of Vinorelbine tartrate injection is contraindicated in patients with pretreatment granulocyte counts <1000 cells/mm3. (SeeWARNINGS.)

Warnings

Vinorelbine 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 Vinorelbine 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 Vinorelbine. Vinorelbine should not be administered to patients with granulocyte counts <1000 cells/mm3. Patients developing severe granulocytopenia should be monitored carefully for evidence of infection and/or fever. SeeDOSAGE AND ADMINISTRATIONfor recommended dose adjustments for granulocytopenia.

Acute shortness of breath and severe bronchospasm have been reported infrequently, following the administration of Vinorelbine 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 Vinorelbine. 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.

Vinorelbine 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

Vinorelbine 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 Vinorelbine 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 Vinorelbine.

Precautions

General

Most drug-related adverse events of Vinorelbine are reversible. If severe adverse events occur, Vinorelbine should be reduced in dosage or discontinued and appropriate corrective measures taken. Reinstitution of therapy with Vinorelbine should be carried out with caution and alertness as to possible recurrence of toxicity.

Vinorelbine 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. (SeeDOSAGE AND ADMINISTRATION.)

Administration of Vinorelbine to patients with prior radiation therapy may result in radiation recall reactions. (SeeADVERSE REACTIONSandDrug 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 Vinorelbine.

Care must be taken to avoid contamination of the eye with concentrations of Vinorelbine 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 Vinorelbine 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 if 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 Vinorelbine. (SeeADVERSE REACTIONS: Hematologic.)

Hepatic

There is no evidence that the toxicity of Vinorelbine 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 Vinorelbine. Because clinical experience in patients with severe liver disease is limited, caution should be exercised when administering Vinorelbine to patients with severe hepatic injury or impairment. (SeeDOSAGE AND ADMINISTRATION.)

Drug Interactions

Acute pulmonary reactions have been reported with Vinorelbine 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 Vinorelbine used in combination with cisplatin is significantly higher than with single-agent Vinorelbine. Patients who receive Vinorelbine and paclitaxel, either concomitantly or sequentially, should be monitored for signs and symptoms of neuropathy. Administration of Vinorelbine to patients with prior or concomitant radiation therapy may result in radiosensitizing 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 Vinorelbine 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

SeeWARNINGSsection.

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 Vinorelbine, it is recommended that nursing be discontinued in women who are receiving therapy with Vinorelbine.

Pediatric Use

Safety and effectiveness of Vinorelbine tartrate injection 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 adult patients

Geriatric Use

Of the total number of patients in North American clinical studies of IV Vinorelbine, 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 Vinorelbine is used as a single agent or in combination. Adverse reactions from studies with single-agent and combination use of Vinorelbine are summarized in Tables 2–4.

Single-Agent Vinorelbine

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 Vinorelbine as a single agent in 3 clinical studies. The dosing schedule in each study was 30 mg/m2 Vinorelbine on a weekly basis.

Table 2 Summary of Adverse Events in 365 Patients Receiving Single-Agent Vinorelbine Tartrate Injection*†

Adverse Event			All Patients (n = 365)		NSCLC (n = 143)
* 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.
Bone Marrow
Granulocytopenia	<2000 cells/mm3		90%		80%
	<500 cells/mm3		36%		29%
Leukopenia	<4000 cells/mm3		92%		81%
	<1000 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%
Adverse Event	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 Vinorelbine. Dose adjustments are required for hematologic toxicity and hepatic insufficiency. (SeeDOSAGE 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 Vinorelbine. 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 Vinorelbine.

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 anticancer vinca alkaloids, Vinorelbine 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 Vinorelbine. Due to the low incidence of severe nausea and vomiting with single-agent Vinorelbine, 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%. (SeeWARNINGS.) Interstitial pulmonary chan

Maxalt

Dosage Form: tablet, orally disintegrating
FULL PRESCRIBING INFORMATION

Indications and Usage for Maxalt

 Maxalt® and Maxalt-MLT® are indicated for the acute treatment of migraine with or without aura in adults and in pediatric patients 6 to 17 years old.

Limitations of Use

• Maxalt should only be used where a clear diagnosis of migraine has been established. If a patient has no response for the first migraine attack treated with Maxalt, the diagnosis of migraine should be reconsidered before Maxalt is administered to treat any subsequent attacks.


• Maxalt is not indicated for use in the management of hemiplegic or basilar migraine [see Contraindications (4)].


• Maxalt is not indicated for the prevention of migraine attacks.


• Safety and effectiveness of Maxalt have not been established for cluster headache.

Maxalt Dosage and Administration

Dosing Information in Adults

The recommended starting dose of Maxalt is either 5 mg or 10 mg for the acute treatment of migraines in adults. The 10-mg dose may provide a greater effect than the 5-mg dose, but may have a greater risk of adverse reactions [see Clinical Studies (14.1)].

Redosing in Adults

Although the effectiveness of a second dose or subsequent doses has not been established in placebo-controlled trials, if the migraine headache returns, a second dose may be administered 2 hours after the first dose. The maximum daily dose should not exceed 30 mg in any 24-hour period. The safety of treating, on average, more than four headaches in a 30-day period has not been established.

Dosing Information in Pediatric Patients (Age 6 to 17 Years)

 Dosing in pediatric patients is based on the patient's body weight. The recommended dose of Maxalt is 5 mg in patients weighing less than 40 kg (88 lb), and 10 mg in patients weighing 40 kg (88 lb) or more.

 The efficacy and safety of treatment with more than one dose of Maxalt within 24 hours in pediatric patients 6 to 17 years of age have not been established.

Administration of Maxalt-MLT Orally Disintegrating Tablets

For Maxalt-MLT Orally Disintegrating Tablets, administration with liquid is not necessary. Orally disintegrating tablets are packaged in a blister within an outer aluminum pouch and patients should not remove the blister from the outer pouch until just prior to dosing. The blister pack should then be peeled open with dry hands and the orally disintegrating tablet placed on the tongue, where it will dissolve and be swallowed with the saliva.

Dosage Adjustment for Patients on Propranolol

Adult Patients

In adult patients taking propranolol, only the 5-mg dose of Maxalt is recommended, up to a maximum of 3 doses in any 24-hour period (15 mg) [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

Pediatric Patients

For pediatric patients weighing ≥40 kg (88 lb) taking propranolol, only a single 5-mg dose of Maxalt is recommended (maximum dose of 5 mg in a 24-hour period). Maxalt should not be prescribed to propranolol-treated pediatric patients who weigh less than 40 kg (88 lb) [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

Dosage Forms and Strengths

Maxalt Tablets

• 5 mg tablets are pale pink, capsule-shaped, compressed tablets coded MRK on one side and 266 on the other.


• 10 mg tablets are pale pink, capsule-shaped, compressed tablets coded Maxalt on one side and MRK 267 on the other.

Maxalt-MLT Orally Disintegrating Tablets

• 5 mg orally disintegrating tablets are white to off-white, round lyophilized tablets debossed with a modified triangle on one side.


• 10 mg orally disintegrating tablets are white to off-white, round lyophilized tablets debossed with a modified square on one side.

Contraindications

Maxalt is contraindicated in patients with:

• Ischemic coronary artery disease (angina pectoris, history of myocardial infarction, or documented silent ischemia), or other significant underlying cardiovascular disease [see Warnings and Precautions (5.1)].


• Coronary artery vasospasm including Prinzmetal's angina [see Warnings and Precautions (5.1)].


• History of stroke or transient ischemic attack (TIA) [see Warnings and Precautions (5.4)].


• Peripheral vascular disease (PVD) [see Warnings and Precautions (5.5)].


• Ischemic bowel disease [see Warnings and Precautions (5.5)].


• Uncontrolled hypertension [see Warnings and Precautions (5.8)].


• Recent use (i.e., within 24 hours) of another 5-HT1 agonist, ergotamine-containing medication, or ergot-type medication (such as dihydroergotamine or methysergide) [see Drug Interactions (7.2 and 7.3)].


• Hemiplegic or basilar migraine.


• Concurrent administration or recent discontinuation (i.e., within 2 weeks) of a MAO-A inhibitor [see Drug Interactions (7.5) and Clinical Pharmacology (12.3)].


• Hypersensitivity to Maxalt or Maxalt-MLT (angioedema and anaphylaxis seen) [see Adverse Reactions (6.2)].

Warnings and Precautions

Myocardial Ischemia, Myocardial Infarction, and Prinzmetal's Angina

Maxalt should not be given to patients with ischemic or vasospastic coronary artery disease. There have been rare reports of serious cardiac adverse reactions, including acute myocardial infarction, occurring within a few hours following administration of Maxalt. Some of these reactions occurred in patients without known coronary artery disease (CAD). 5-HT1 agonists including Maxalt may cause coronary artery vasospasm (Prinzmetal's Angina), even in patients without a history of CAD.

Triptan-naïve patients who have multiple cardiovascular risk factors (e.g., increased age, diabetes, hypertension, smoking, obesity, strong family history of CAD) should have a cardiovascular evaluation prior to receiving Maxalt. If there is evidence of CAD or coronary artery vasospasm, Maxalt should not be administered [see Contraindications (4)]. For patients who have a negative cardiovascular evaluation, consideration should be given to administration of the first Maxalt dose in a medically-supervised setting and performing an electrocardiogram (ECG) immediately following Maxalt administration. Periodic cardiovascular evaluation should be considered in intermittent long-term users of Maxalt who have cardiovascular risk factors.

Arrhythmias

Life-threatening disturbances of cardiac rhythm, including ventricular tachycardia and ventricular fibrillation leading to death, have been reported within a few hours following the administration of 5-HT1 agonists. Discontinue Maxalt if these disturbances occur.

Chest, Throat, Neck and/or Jaw Pain/Tightness/Pressure

As with other 5-HT1 agonists, sensations of tightness, pain, pressure, and heaviness in the precordium, throat, neck and jaw commonly occur after treatment with Maxalt and are usually non-cardiac in origin. However, if a cardiac origin is suspected, patients should be evaluated. Patients shown to have CAD and those with Prinzmetal's variant angina should not receive 5-HT1 agonists.

Cerebrovascular Events

Cerebral hemorrhage, subarachnoid hemorrhage, and stroke have occurred in patients treated with 5-HT1 agonists, and some have resulted in fatalities. In a number of cases, it appears possible that the cerebrovascular events were primary, the 5-HT1 agonist having been administered in the incorrect belief that the symptoms experienced were a consequence of migraine, when they were not. Also, patients with migraine may be at increased risk of certain cerebrovascular events (e.g., stroke, hemorrhage, transient ischemic attack). Discontinue Maxalt if a cerebrovascular event occurs.

As with other acute migraine therapies, before treating headaches in patients not previously diagnosed as migraineurs, and in migraineurs who present with atypical symptoms, care should be taken to exclude other potentially serious neurological conditions. Maxalt should not be administered to patients with a history of stroke or transient ischemic attack [see Contraindications (4)].

Other Vasospasm Reactions

5-HT1 agonists, including Maxalt, may cause non-coronary vasospastic reactions, such as peripheral vascular ischemia, gastrointestinal vascular ischemia and infarction (presenting with abdominal pain and bloody diarrhea), splenic infarction, and Raynaud's syndrome. In patients who experience symptoms or signs suggestive of non-coronary vasospasm reaction following the use of any 5-HT1 agonist, the suspected vasospasm reaction should be ruled out before receiving additional Maxalt doses.

Reports of transient and permanent blindness and significant partial vision loss have been reported with the use of 5-HT1 agonists. Since visual disorders may be part of a migraine attack, a causal relationship between these events and the use of 5-HT1 agonists have not been clearly established.

Medication Overuse Headache

Overuse of acute migraine drugs (e.g., ergotamine, triptans, opioids, or a combination of drugs for 10 or more days per month) may lead to exacerbation of headache (medication overuse headache). Medication overuse headache may present as migraine-like daily headaches, or as a marked increase in frequency of migraine attacks. Detoxification of patients, including withdrawal of the overused drugs, and treatment of withdrawal symptoms (which often includes a transient worsening of headache) may be necessary.

Serotonin Syndrome

Serotonin syndrome may occur with triptans, including Maxalt particularly during co-administration with selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and MAO inhibitors [see Drug Interactions (7.5)]. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The onset of symptoms can occur within minutes to hours of receiving a new or a greater dose of a serotonergic medication. Maxalt treatment should be discontinued if serotonin syndrome is suspected [see Drug Interactions (7.4) and Patient Counseling Information (17)].

Increase in Blood Pressure

Significant elevation in blood pressure, including hypertensive crisis with acute impairment of organ systems, has been reported on rare occasions in patients with and without a history of hypertension receiving 5-HT1 agonists, including Maxalt. In healthy young adult male and female patients who received maximal doses of Maxalt (10 mg every 2 hours for 3 doses), slight increases in blood pressure (approximately 2-3 mmHg) were observed. Maxalt is contraindicated in patients with uncontrolled hypertension [see Contraindications (4)].

Adverse Reactions

The following adverse reactions are discussed in more detail in other sections of the labeling:

• Myocardial Ischemia, Myocardial Infarction, and Prinzmetal's Angina [see Warnings and Precautions (5.1)].


• Arrhythmias [see Warnings and Precautions (5.2)].


• Chest and or Throat, Neck and/or Jaw Pain/Tightness/Pressure [see Warnings and Precautions (5.3)].


• Cerebrovascular Events [see Warnings and Precautions (5.4)].


• Other Vasospasm Reactions [see Warnings and Precautions (5.5)].


• Medication Overuse Headache [see Warnings and Precautions (5.6)].


• Serotonin Syndrome [see Warnings and Precautions (5.7)].


• Increase in Blood Pressure [see Warnings and Precautions (5.8)].

Clinical Trials Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

Adults

Incidence in Controlled Clinical Trials

Adverse reactions to Maxalt were assessed in controlled clinical trials that included over 3700 adult patients who received single or multiple doses of Maxalt Tablets. The most common adverse reactions during treatment with Maxalt (≥5% in either treatment group and greater than placebo) were asthenia/fatigue, somnolence, pain/pressure sensation and dizziness. These adverse reactions appeared to be dose related.

Table 1 lists the adverse reactions (incidence ≥2% and greater than placebo) after a single dose of Maxalt in adults.

Table 1: Incidence (≥2% and Greater than Placebo) of Adverse Reactions After a Single Dose of Maxalt Tablets or Placebo in Adults

	% of Patients
Adverse Reactions	Maxalt 5 mg (N=977)	Maxalt 10 mg (N=1167)	Placebo (N=627)
Atypical Sensations	4	5	4
Paresthesia	3	4	<2
Pain and other Pressure Sensations	6	9	3
Chest Pain:
tightness/pressure and/or heaviness	<2	3	1
Neck/throat/jaw:
pain/tightness/pressure	<2	2	1
Regional Pain:
tightness/pressure and/or heaviness	<1	2	0
Pain, location unspecified	3	3	<2
Digestive	9	13	8
Dry Mouth	3	3	1
Nausea	4	6	4
Neurological	14	20	11
Dizziness	4	9	5
Headache	<2	2	<1
Somnolence	4	8	4
Other
Asthenia/fatigue	4	7	2

The frequencies of adverse reactions in clinical trials did not increase when up to three doses were taken within 24 hours. Adverse reaction frequencies were also unchanged by concomitant use of drugs commonly taken for migraine prophylaxis (including propranolol), oral contraceptives, or analgesics. The incidences of adverse reactions were not affected by age or gender. There were insufficient data to assess the impact of race on the incidence of adverse reactions.

Other Events Observed in Association with the Administration of Maxalt in Adults

In the following section, the frequencies of less commonly reported adverse events are presented that were not reported in other sections of the labeling. Because the reports include events observed in open studies, the role of Maxalt in their causation cannot be reliably determined. Furthermore, variability associated with adverse event reporting, the terminology used to describe adverse events, limit the value of the quantitative frequency estimates provided. Event frequencies are calculated as the number of patients who used Maxalt and reported an event divided by the total number of patients exposed to Maxalt (N=3716). All reported events occurred at an incidence ≥1%, or are believed to be reasonably associated with the use of the drug. Events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are those defined as those occurring in at least (>)1/100 patients; infrequent adverse experiences are those occurring in 1/100 to 1/1000 patients; and rare adverse experiences are those occurring in fewer than 1/1000 patients.

General: Infrequent was facial edema. Rare were syncope and edema/swelling.

Atypical Sensations: Frequent were warm sensations.

Cardiovascular: Frequent was palpitation. Infrequent were tachycardia, cold extremities, and bradycardia.

Digestive: Frequent were diarrhea and vomiting. Infrequent were dyspepsia, tongue edema and abdominal distention.

Musculoskeletal: Infrequent were muscle weakness, stiffness, myalgia and muscle cramp/spasm.

Neurological/Psychiatric: Frequent were hypoesthesia, euphoria and tremor. Infrequent were vertigo, insomnia, confusion/disorientation, gait abnormality, memory impairment, and agitation.

Respiratory: Frequent was dyspnea. Infrequent was pharyngeal edema.

Special Senses: Infrequent were blurred vision and tinnitus. Rare was eye swelling.

Skin and Skin Appendage: Frequent was flushing. Infrequent were sweating, pruritus, rash, and urticaria. Rare was erythema, hot flashes.

The adverse reaction profile seen with Maxalt-MLT Orally Disintegrating Tablets was similar to that seen with Maxalt Tablets.

Pediatric Patients 6 to 17 Years of Age

Incidence in Controlled Clinical Trials in Pediatric Patients

Adverse reactions to Maxalt-MLT were assessed in a controlled clinical trial in the acute treatment of migraines (Study 7) that included a total of 1382 pediatric patients 6-17 years of age, of which 977 (72%) administered at least one dose of study treatment (Maxalt-MLT and/or placebo) [see Clinical Studies (14.2)]. The incidence of adverse reactions reported for pediatric patients in the acute clinical trial was similar in patients who received Maxalt to those who received placebo. The adverse reaction pattern in pediatric patients is expected to be similar to that in adults.

Other Events Observed in Association with the Administration of Maxalt-MLT in Pediatric Patients

In the following section, the frequencies of less commonly reported adverse events are presented. Because the reports include events observed in open studies, the role of Maxalt-MLT in their causation cannot be reliably determined. Furthermore, variability associated with adverse event reporting, the terminology used to describe adverse events, limit the value of the quantitative frequency estimates provided.

Event frequencies are calculated as the number of pediatric patients 6 to 17 years of age who used Maxalt-MLT and reported an event divided by the total number of patients exposed to Maxalt-MLT (N=1068). All reported events occurred at an incidence ≥1%, or are believed to be reasonably associated with the use of the drug. Events are further classified within system organ class and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are those occurring in (>)1/100 pediatric patients; infrequent adverse experiences are those occurring in 1/100 to 1/1000 pediatric patients; and rare adverse experiences are those occurring in fewer than 1/1000 patients.

General: Frequent was fatigue.

Ear and labyrinth disorders: Infrequent was hypoacusis.

Gastrointestinal disorders: Frequent was abdominal discomfort.

Nervous system disorders: Infrequent were coordination abnormal, disturbance in attention, and presyncope.

Psychiatric disorders: Infrequent was hallucination.

Postmarketing Experience

The following section enumerates potentially important adverse events that have occurred in clinical practice and which have been reported spontaneously to various surveillance systems. The events enumerated include all except those already listed in other sections of the labeling or those too general to be informative. Because the reports cite events reported spontaneously from worldwide postmarketing experience, frequency of events and the role of Maxalt in their causation cannot be reliably determined.

Neurological/Psychiatric: Seizure.

General: Allergic conditions including anaphylaxis/anaphylactoid reaction, angioedema, wheezing, and toxic epidermal necrolysis [see Contraindications (4)].

Special Senses: Dysgeusia.

Drug Interactions

Propranolol

The dose of Maxalt should be adjusted in propranolol-treated patients, as propranolol has been shown to increase the plasma AUC of rizatriptan by 70% [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].

Ergot-Containing Drugs

Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because these effects may be additive, use of ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) and Maxalt within 24 hours is contraindicated [see Contraindications (4)].

Other 5-HT1 Agonists

Because their vasospastic effects may be additive, co-administration of Maxalt and other 5-HT1 agonists within 24 hours of each other is contraindicated [see Contraindications (4)].

SSRIs/SNRIs and Serotonin Syndrome

Cases of serotonin syndrome have been reported during co-administration of triptans and selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) [see Warnings and Precautions (5.7)].

Monoamine Oxidase Inhibitors

Maxalt is contraindicated in patients taking MAO-A inhibitors and non-selective MAO inhibitors. A specific MAO-A inhibitor increased the systemic exposure of rizatriptan and its metabolite [see Contraindications (4) and Clinical Pharmacology (12.3)].

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies in pregnant women. Maxalt should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

In a general reproductive study in rats, birth weights and pre- and post-weaning weight gain were reduced in the offspring of females treated prior to and during mating and throughout gestation and lactation with doses of 10 and 100 mg/kg/day. In a pre- and post-natal developmental toxicity study in rats, an increase in mortality of the offspring at birth and for the first three days after birth, a decrease in pre- and post-weaning weight gain, and decreased performance in a passive avoidance test (which indicates a decrease in learning capacity of the offspring) were observed at doses of 100 and 250 mg/kg/day. The no-effect dose for all of these effects was 5 mg/kg/day, associated with a maternal plasma exposure (AUC) approximately 7.5 times that in humans receiving the MRDD. With doses of 100 and 250 mg/kg/day, the decreases in average weight of both the male and female offspring persisted into adulthood. All effects on the offspring in both studies occurred in the absence of any apparent maternal toxicity.

In embryofetal development studies, no teratogenic effects were observed when pregnant rats and rabbits were administered doses of 100 and 50 mg/kg/day, respectively, during organogenesis. Fetal weights were decreased in conjunction with decreased maternal weight gain at the highest doses tested. The developmental no-effect dose in these studies was 10 mg/kg/day in both rats and rabbits (maternal exposures approximately 15 times human exposure at the MRDD). Toxicokinetic studies demonstrated placental transfer of drug in both species.

Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., maintains a registry to monitor the pregnancy outcomes of women exposed to Maxalt while pregnant. Healthcare providers are encouraged to report any prenatal exposure to Maxalt by calling the Pregnancy Registry at 1-800-986-8999.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Maxalt is administered to a nursing woman. Rizatriptan is extensively excreted in rat milk, with levels in milk at least 5-fold higher than levels in maternal plasma.

Pediatric Use

Safety and effectiveness in pediatric patients under 6 years of age have not been established.

The efficacy and safety of Maxalt in the acute treatment of migraine in patients aged 6 to 17 years was established in an adequate and well-controlled study [see Clinical Studies (14.2)].

The incidence of adverse reactions reported for pediatric patients in the acute clinical trial was similar in patients who received Maxalt to those who received placebo. The adverse reaction pattern in pediatric patients is expected to be similar to that in adults.

Geriatric Use

Clinical studies of Maxalt did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

Although the pharmacokinetics of rizatriptan were similar in elderly (aged ≥65 years) and in younger adults (n=17), in general, dose selection for an elderly patient should be cautious, starting at the low end of the dosing range. This reflects the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Geriatric patients who have other cardiovascular risk factors (e.g., diabetes, hypertension, smoking, obesity, strong family history of coronary artery disease) should have a cardiovascular evaluation prior to receiving Maxalt [see Warnings and Precautions (5.1)].

Patients with Phenylketonuria

Orally Disintegrating Tablets contain phenylalanine (a component of aspartame). The 5 and 10 mg orally disintegrating tablets contain 1.1 and 2.1 mg phenylalanine, respectively.

Overdosage

No overdoses of Maxalt were reported during clinical trials in adults.

Some adult patients who received 40 mg of Maxalt either a single dose or as two doses with a 2-hour interdose interval had dizziness and somnolence.

In a clinical pharmacology study in which 12 adult subjects received Maxalt, at total cumulative doses of 80 mg (given within four hours), two of the subjects experienced syncope, dizziness, bradycardia including third degree AV block, vomiting, and/or incontinence.

In the long-term, open label study, involving 606 treated pediatric migraineurs 12 to 17 years of age (of which 432 were treated for at least 12 months), 151 patients (25%) took two 10-mg doses of Maxalt-MLT within a 24-hour period. Adverse reactions for 3 of these patients included abdominal discomfort, fatigue, and dyspnea.

In addition, based on the pharmacology of Maxalt, hypertension or myocardial ischemia could occur after overdosage. Gastrointestinal decontamination, (i.e., gastric lavage followed by activated charcoal) should be considered in patients suspected of an overdose with Maxalt. Clinical and electrocardiographic monitoring should be continued for at least 12 hours, even if clinical symptoms are not observed.

The effects of hemo- or peritoneal dialysis on serum concentrations of rizatriptan are unknown.

Maxalt Description

Maxalt contains rizatriptan benzoate, a selective 5-hydroxytryptamine1B/1D (5-HT1B/1D) receptor agonist. Rizatriptan benzoate is described chemically as: N,N-dimethyl-5-(1H-1,2,4-triazol-1-ylmethyl)-1H-indole-3-ethanamine monobenzoate and its structural formula is:

Its empirical formula is C15H19N5•C7H6O2, representing a molecular weight of the free base of 269.4. Rizatriptan benzoate is a white to off-white, crystalline solid that is soluble in water at about 42 mg per mL (expressed as free base) at 25°C.

Maxalt Tablets and Maxalt-MLT Orally Disintegrating Tablets are available for oral administration in strengths of 5 and 10 mg (corresponding to 7.265 mg or 14.53 mg of the benzoate salt, respectively). Each compressed tablet contains the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, pregelatinized starch, ferric oxide (red), and magnesium stearate.

Each lyophilized orally disintegrating tablet contains the following inactive ingredients: gelatin, mannitol, glycine, aspartame, and peppermint flavor.

Maxalt - Clinical Pharmacology

Mechanism of Action

Rizatriptan binds with high affinity to human cloned 5-HT1B/1D receptors. Maxalt presumably exerts its therapeutic effects in the treatment of migraine headache by binding to 5-HT1B/1D receptors located on intracranial blood vessels and sensory nerves of the trigeminal system.

Pharmacokinetics

Absorption

Rizatriptan is completely absorbed following oral administration. The mean oral absolute bioavailability of the Maxalt Tablet is about 45%, and mean peak plasma concentrations (Cmax) are reached in approximately 1-1.5 hours (Tmax). The presence of a migraine headache did not appear to affect the absorption or pharmacokinetics of rizatriptan. Food has no significant effect on the bioavailability of rizatriptan but delays the time to reach peak concentration by an hour. In clinical trials, Maxalt was administered without regard to food.

The bioavailability and Cmax of rizatriptan were similar following administration of Maxalt Tablets and Maxalt-MLT Orally Disintegrating Tablets, but the rate of absorption is somewhat slower with Maxalt-MLT, with Tmax delayed by up to 0.7 hour. AUC of rizatriptan is approximately 30% higher in females than in males. No accumulation occurred on multiple dosing.

Distribution

The mean volume of distribution is approximately 140 liters in male subjects and 110 liters in female subjects. Rizatriptan is minimally bound (14%) to plasma proteins.

Metabolism

The primary route of rizatriptan metabolism is via oxidative deamination by monoamine oxidase-A (MAO-A) to the indole acetic acid metabolite, which is not active at the 5-HT1B/1D receptor. N-monodesmethyl-rizatriptan, a metabolite with activity similar to that of parent compound at the 5-HT1B/1D receptor, is formed to a minor degree. Plasma concentrations of N-monodesmethyl-rizatriptan are approximately 14% of those of parent compound, and it is eliminated at a similar rate. Other minor metabolites, the N-oxide, the 6-hydroxy compound, and the sulfate conjugate of the 6-hydroxy metabolite are not active at the 5-HT1B/1D receptor.

Elimination

The total radioactivity of the administered dose recovered over 120 hours in urine and feces was 82% and 12%, respectively, following a single 10 mg oral administration of 14C-rizatriptan. Following oral administration of 14C-rizatriptan, rizatriptan accounted for about 17% of circulating plasma radioactivity. Approximately 14% of an oral dose is excreted in urine as unchanged rizatriptan while 51% is excreted as indole acetic acid metabolite, indicating substantial first pass metabolism.

The plasma half-life of rizatriptan in males and females averages 2-3 hours.

Cytochrome P450 Isoforms

Rizatriptan is not an inhibitor of the activities of human liver cytochrome P450 isoforms 3A4/5, 1A2, 2C9, 2C19, or 2E1; rizatriptan is a competitive inhibitor (Ki=1400 nM) of cytochrome P450 2D6, but only at high, clinically irrelevant concentrations.

Special Populations

Geriatric: Rizatriptan pharmacokinetics in healthy elderly non-migraineur volunteers (age 65-77 years) were similar to those in younger non-migraineur volunteers (age 18-45 years).

Pediatric: The pharmacokinetics of rizatriptan was determined in pediatric migraineurs 6 to 17 years of age. Exposures following single dose administration of 5 mg Maxalt-MLT to pediatric patients weighing 20-39 kg (44-87 lb) or 10 mg Maxalt-MLT to pediatric patients weighing ≥40 kg (88 lb) were similar to those observed following single dose administration of 10 mg Maxalt-MLT to adults.

Gender: The mean AUC0-∞ and Cmax of rizatriptan (10 mg orally) were about 30% and 11% higher in females as compared to males, respectively, while Tmax occurred at approximately the same time.

Hepatic impairment: Following oral administration in patients with hepatic impairment caused by mild to moderate alcoholic cirrhosis of the liver, plasma concentrations of rizatriptan were similar in patients with mild hepatic insufficiency compared to a control group of subjects with normal hepatic function; plasma concentrations of rizatriptan were approximately 30% greater in patients with moderate hepatic insufficiency.

Renal impairment: In patients with renal impairment (creatinine clearance 10-60 mL/min/1.73 m2), the AUC0-∞ of rizatriptan was not significantly different from that in subjects with normal renal function. In hemodialysis patients, (creatinine clearance <2 mL/min/1.73 m2), however, the AUC for rizatriptan was approximately 44% greater than that in patients with normal renal function.

Race: Pharmacokinetic data revealed no significant differences between African American and Caucasian subjects.

Drug Interactions

[See also Drug Interactions (7).]

Monoamine oxidase inhibitors: Rizatriptan is principally metabolized via monoamine oxidase, 'A' subtype (MAO-A). Plasma concentrations of rizatriptan may be increased by drugs that are selective MAO-A inhibitors (e.g., moclobemide) or nonselective MAO inhibitors [type A and B] (e.g., isocarboxazid, phenelzine, tranylcypromine, and pargyline). In a drug interaction study, when Maxalt 10 mg was administered to subjects (n=12) receiving concomitant therapy with the selective, reversible MAO-A inhibitor, moclobemide 150 mg t.i.d., there were mean increases in rizatriptan AUC and Cmax of 119% and 41% respectively; and the AUC of the active N-monodesmethyl metabolite of rizatriptan was increased more than 400%. The interaction would be expected to be greater with irreversible MAO inhibitors. No pharmacokinetic interaction is anticipated in patients receiving selective MAO-B inhibitors [see Contraindications (4) and Drug Interactions (7.5)].

Propranolol: In a study of concurrent administration of propranolol 240 mg/day and a single dose of rizatriptan 10 mg in healthy adult subjects (n=11), mean plasma AUC for rizatriptan was increased by 70% during propranolol administration, and a four-fold increase was observed in one subject. The AUC of the active N-monodesmethyl metabolite of rizatriptan was not affected by propranolol [see Dosage and Administration (2.4) and Drug Interactions (7.1)].

Nadolol/Metoprolol: In a drug interactions study, effects of multiple doses of nadolol 80 mg or metoprolol 100 mg every 12 hours on the pharmacokinetics of a single dose of 10 mg rizatriptan were evaluated in healthy subjects (n=12). No pharmacokinetic interactions were observed.

Paroxetine: In a study of the interaction between the selective serotonin reuptake inhibitor (SSRI) paroxetine 20 mg/day for two weeks and a single dose of Maxalt 10 mg in healthy subjects (n=12), neither the plasma concentrations of rizatriptan nor its safety profile were affected by paroxetine [see Warnings and Precautions (5.7), Drug Interactions (7.4), and Patient Counseling Information (17)].

Oral contraceptives: In a study of concurrent administration of an oral contraceptive during 6 days of administration of Maxalt (10-30 mg/day) in healthy female volunteers (n=18), rizatriptan did not affect plasma concentrations of ethinyl estradiol or norethindrone.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis: Oral carcinogenicity studies were conducted in mice (100 weeks) and rats (106 weeks) at doses of up to 125 mg/kg/day. Plasma exposures (AUC) at the highest dose tested were approximately 150 (mice) and 240 times (rats) that in humans at the maximum recommended daily dose (MRDD) of 30 mg/day. There was no evidence of an increase in tumor incidence related to rizatriptan in either species.

Mutagenesis: Rizatriptan was neither mutagenic nor clastogenic in a battery of in vitro and in vivo genetic toxicity studies, including: the microbial mutagenesis (Ames) assay, in vitro mammalian cell mutagenesis and chromosomal aberration assays, and the in vivo chromosomal aberration assay in mouse.

Impairment of Fertility: In a fertility study in rats, altered estrus cyclicity and delays in time to mating were observed in females treated orally with 100 mg/kg/day rizatriptan. The no-effect dose was 10 mg/kg/day (approximately 15 times the human exposure at the MRDD). There were no other fertility-related effects in the female rats. There was no impairment of fertility or reproductive performance in male rats treated with up to 250 mg/kg/day (approximately 550 times the human exposure at the MRDD).

Clinical Studies

Adults

The efficacy of Maxalt Tablets was established in four multicenter, randomized, placebo-controlled trials. Patients enrolled in these studies were primarily female (84%) and Caucasian (88%), with a mean age of 40 years (range of 18 to 71). Patients were instructed to treat a moderate to severe headache. Headache response, defined as a reduction of moderate or severe headache pain to no or mild headache pain, was assessed for up to 2 hours (Study 1) or up to 4 hours after dosing (Studies 2, 3 and 4). Associated symptoms of nausea, photophobia, and phonophobia and maintenance of response up to 24 hours post-dose were evaluated. A second dose of Maxalt Tablets was allowed 2 to 24 hours after dosing for treatment of recurrent headache in Studies 1 and 2. Additional analgesics and/or antiemetics were allowed 2 hours after initial treatment for rescue in all four studies.

In all studies, the percentage of patients achieving headache response 2 hours after treatment was significantly greater in patients who received either Maxalt 5 or 10 mg compared to those who received placebo. In a separate study, doses of 2.5 mg were not different from placebo. Doses greater than 10 mg were associated with an increased incidence of adverse effects. The results from the four controlled studies are summarized in Table 2.

Table 2: Response Rates 2 Hours Following Treatment of Initial Headache in Studies 1, 2, 3, and 4

Study	Placebo	Maxalt Tablets 5 mg	Maxalt Tablets 10 mg
* p-value <0.05 in comparison with placebo † p-value <0.05 in comparison with 5 mg ‡ Results for initial headache only.
1	35% (n=304)	62%* (n=458)	71%*,† (n=456)
2‡	37% (n=82)	—	77%* (n=320)
3	23% (n=80)	63%* (n=352)	—
4	40% (n=159)	60%* (n=164)	67%* (n=385)

Comparisons of drug performance based upon results obtained in different clinical trials may not be reliable. Because studies are conducted at different times, with different samples of patients, by different investigators, employing different criteria and/or different interpretations of the same criteria, under different conditions (dose, dosing regimen, etc.), quantitative estimates of treatment response and the timing of response may be expected to vary considerably from study to study.

The estimated probability of achieving an initial headache response within 2 hours following treatment in pooled Studies 1, 2, 3, and 4 is depicted in Figure 1.

Figure 1: Estimated Probability of Achieving an Initial Headache Response by 2 Hours in Pooled Studies 1, 2, 3, and 4*

* Figure 1 shows the Kaplan-Meier plot of the probability over time of obtaining headache response (no or mild pain) following treatment with Maxalt or placebo. The averages displayed are based on pooled data from 4 placebo-controlled, outpatient trials providing evidence of efficacy (Studies 1, 2, 3, and 4). Patients taking additional treatment or not achieving headache response prior to 2 hours were censored at 2 hours.

For patients with migraine-associated photophobia, phonophobia, and nausea at baseline, there was a decreased incidence of these symptoms following administration of Maxalt compared to placebo.

Two to 24 hours following the initial dose of study treatment, patients were allowed to use additional treatment for pain response in the form of a second dose of study treatment or other medication. The estimated probability of patients taking a second dose or other medication for migraine over the 24 hours following the initial dose of study treatment is summarized in Figure 2.

Figure 2: Estimated Probability of Patients Taking a Second Dose of Maxalt Tablets or Other Medication for Migraines Over the 24 Hours Following the Initial Dose of Study Treatment in Pooled Studies 1, 2, 3, and 4*

* This Kaplan-Meier plot is based on data obtained in 4 placebo-controlled outpatient clinical trials (Studies 1, 2, 3, and 4). Patients not using additional treatments were censored at 24 hours. The plot includes both patients who had headache response at 2 hours and those who had no response to the initial dose. Rem

Urelle

hyoscyamine sulfate, methenamine, methylene blue, phenyl salicylate, and sodium phosphate, monobasic, monohydrate

Dosage Form: tablet
Urelle® Urinary Antiseptic

Urelle Description

Urelle® tablets for oral administration are supplied as navy blue round tablets with “A-002” debossed on one side.

Each Tablet Contains:

Hyoscyamine Sulfate 0.12 mg

Methenamine 81.0 mg

Methylene Blue 10.8 mg

Phenyl Salicylate 32.4 mg

Sodium Phosphate Monobasic 40.8 mg

INACTIVE INGREDIENTS

Corn Starch, Dicalcium Phosphate, FD&C Blue #2/Indigo Carmine Aluminum Lake, Magnesium Stearate, Microcrystalline Cellulose, Polyethylene Glycol, Polyvinyl Alcohol, Talc, Titanium Dioxide.

Indications and Usage for Urelle

Urelle®  is indicated for the treatment of symptoms of irritative voiding. Indicated for the relief of local symptoms, such as inflammation, hypermotility, and pain, which accompany lower urinary tract infections. Indicated for the relief of urinary tract symptoms caused by diagnostic procedures.

Contraindications

Hypersensitivity to any of the ingredients is possible. Risk - benefit should be carefully considered when the following medical problems exist: cardiac disease (especially cardiac arrhythmias, congestive heart failure, coronary heart disease, mitral stenosis); gastrointestinal tract obstructive disease; glaucoma; myasthenia gravis; acute urinary retention may be precipitated in obstructive uropathy (such as bladder neck obstruction due to prostatic hypertrophy).

Warnings

If rapid pulse, dizziness, or blurring of vision occurs, discontinue use immediately.

Patients should be advised that urine will be colored blue when taking this medication.

Do not exceed recommended dosage.

Precautions

Cross sensitivity and/or related problems  - patients intolerant of belladonna alkaloids or salicylates may be intolerant of this medication also. Delay in gastric emptying could complicate the management of gastric ulcers.

Urelle® contains methylene blue. Methylene blue should NOT be given to patients taking serotonergic drugs.

Drug Interactions

Although the exact mechanism of this drug interaction is unknown, methylene blue inhibits the action of monoamine oxidase A— an enzyme responsible for breaking down serotonin in the brain. It is believed that when methylene blue is given to patients taking serotonergic psychiatric medications, high levels of serotonin can build up in the brain, causing toxicity. This is referred to as Serotonin Syndrome. Signs and symptoms of Serotonin Syndrome include mental changes (confusion, hyperactivity, memory problems), muscle twitching, excessive sweating, shivering or shaking, diarrhea, trouble with coordination, and/or fever.

Additional Information for Healthcare Professionals

Methylene blue can interact with serotonergic psychiatric medications and cause serious CNS toxicity.

In emergency situations requiring life-threatening or urgent treatment with methylene blue (as described above), the availability of alternative interventions should be considered and the benefit of methylene blue treatment should be weighed against the risk of serotonin toxicity. If methylene blue must be administered to a patient receiving a serotonergic drug, the serotonergic drug must be immediately stopped, and the patient should be closely monitored for emergent symptoms of CNS toxicity for two weeks (five weeks if fluoxetine [Prozac] was taken), or until 24 hours after the last dose of methylene blue, whichever comes first.

In non-emergency situations when non-urgent treatment with methylene blue is contemplated and planned, the serotonergic psychiatric medication should be stopped to allow its activity in the brain to dissipate. Most serotonergic psychiatric drugs should be stopped at least 2 weeks in advance of methylene blue treatment. Fluoxetine (Prozac), which has a longer half-life compared to similar drugs, should be stopped at least 5 weeks in advance.

Treatment with the serotonergic psychiatric medication may be resumed 24 hours after the last dose of methylene blue.

Serotonergic psychiatric medications should not be started in a patient receiving methylene blue. Wait until 24 hours after the last dose of methylene blue before starting the antidepressant.

Educate your patients to recognize the symptoms of serotonin toxicity or CNS toxicity and advise them to contact a healthcare professional immediately if they experience any symptoms while taking serotonergic psychiatric medications or methylene blue.

Report adverse events involving methylene blue to the FDA MedWatch program by visiting www.fda.gov/medwatch or calling 1-800-FDA-1088. For more information on Urelle®, call 877 329 2256.

Urelle Dosage and Administration

Adults – One tablet orally 4 times per day followed by liberal fluid intake.

Pediatric – Dosage must be individualized by a physician for older children. Urelle® is not recommended for use in children 6 years of age or younger.

How is Urelle Supplied

Urelle® tablets for oral administration are supplied in child resistant bottles of 90 tablets (NDC 66663-219-01).

Store at controlled room temperature 20°-25°C (68°-77°F).

Dispense in a tight, light resistant container as defined in the USP.

KEEP THIS AND ALL DRUGS OUT OF THE REACH OF CHILDREN.

Distributed by: AZUR PHARMA, INC. • 1818 Market Street, Suite 2350 • Philadelphia, PA 19103 • www.azurpharma.com

Manufactured by: PureTek Corporation. San Fernando, CA 91340

Urelle®  is a registered trademark of Azur Pharma International II Limited.

To report a serious adverse event or obtain product information, contact (800) 890 3098.

Rx Only

URLLw-11-01

PRINCIPAL DISPLAY PANEL - BOTTLE LABEL

Description: Urelle® tablets for oral administration

are supplied as navy blue round tablets with

"A-002" debossed on one side.

Each Tablet Contains:

Hyoscyamine Sulfate 0.12 mg

Methenamine 81.0 mg

Methylene Blue 10.8 mg

Phenyl Salicylate 32.4 mg

Sodium Phosphate Monobasic 40.8 mg

Dosage: Adults - one tablet orally 4 times per day

followed by liberal fluid intake. Pediatric - Dosage

must be individualized by a physician for older

children. Urelle® is not recommended for use in

children 6 years of age or younger.

Precaution: Contains Methylene Blue and should NOT be

taken with serotonergic psychiatric Medications. For full

product information please refer to www.azurpharma.com

To report a serious adverse event or obtain product

information, contact (800) 890 3098.

Storage: Store at controlled room temperature

20°-25°C (68°-77°F). Dispense in a tight, light

resistant container as defined in the USP.

KEEP OUT OF THE REACH OF CHILDREN.

 90 TABLETS                     NDC 66663-219-01

Urelle®

Urinary Antiseptic

Rx Only

Dist. by: AZUR PHARMA, INC.

1818 Market Street, Suite 2350

Philadelphia, PA 19103

Mfd. by: PureTek Corporation

San Fernando, CA 91340

 Urelle is a registered trademark of Azur Pharma International II Limited.

Note: Patients should be advised

that urine will be colored blue

when taking this medication.

URLLt-10-02

Bottle Label

Urelle  hyoscyamine sulfate, methenamine, methylene blue, phenyl salicylate, and sodium phosphate, monobasic, monohydrate  tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 66663-219 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength HYOSCYAMINE SULFATE (HYOSCYAMINE) HYOSCYAMINE SULFATE 0.12 mg METHENAMINE (METHENAMINE) METHENAMINE 81 mg METHYLENE BLUE (METHYLENE BLUE) METHYLENE BLUE 10.8 mg PHENYL SALICYLATE (PHENYL SALICYLATE) PHENYL SALICYLATE 32.4 mg SODIUM PHOSPHATE, MONOBASIC, MONOHYDRATE (PHOSPHATE ION) SODIUM PHOSPHATE, MONOBASIC, MONOHYDRATE 40.8 mg

Inactive Ingredients Ingredient Name Strength STARCH, CORN   ANHYDROUS DIBASIC CALCIUM PHOSPHATE   FD&C BLUE NO. 2   MAGNESIUM STEARATE   CELLULOSE, MICROCRYSTALLINE   POLYETHYLENE GLYCOL   POLYVINYL ALCOHOL   TALC   TITANIUM DIOXIDE

Product Characteristics Color BLUE (Navy) Score no score Shape ROUND Size 11mm Flavor Imprint Code A002 Contains

Packaging # NDC Package Description Multilevel Packaging 1 66663-219-01 90  In 1 BOTTLE None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
Unapproved drug other		01/01/2002

Labeler - Azur Pharma Inc. (805611071)

Establishment
Name	Address	ID/FEI	Operations
PureTek Corporation		785961046	MANUFACTURE

Revised: 10/2011Azur Pharma Inc.

More Urelle resources

• Urelle Dosage
• Urelle Use in Pregnancy & Breastfeeding
• Drug Images
• Urelle Drug Interactions
• Urelle Support Group
• 0 Reviews for Urelle - Add your own review/rating

• Urelle Concise Consumer Information (Cerner Multum)


• Urelle Advanced Consumer (Micromedex) - Includes Dosage Information


• Prosed EC Advanced Consumer (Micromedex) - Includes Dosage Information


• Prosed/DS MedFacts Consumer Leaflet (Wolters Kluwer)


• Urimax Delayed-Release Tablets MedFacts Consumer Leaflet (Wolters Kluwer)


• Urised MedFacts Consumer Leaflet (Wolters Kluwer)


• Uritact-EC Delayed-Release Tablets MedFacts Consumer Leaflet (Wolters Kluwer)


• Uta MedFacts Consumer Leaflet (Wolters Kluwer)

Compare Urelle with other medications

• Urinary Tract Infection

Ovysmen

Ovysmen may be available in the countries listed below.

UK matches:

• Ovysmen Oral Contraceptive Tablets (SPC)

Ingredient matches for Ovysmen

Ethinylestradiol

Ethinylestradiol is reported as an ingredient of Ovysmen in the following countries:

• Austria


• Belgium


• Luxembourg


• United Kingdom

Norethisterone

Norethisterone is reported as an ingredient of Ovysmen in the following countries:

• Austria


• Belgium


• Luxembourg


• United Kingdom

International Drug Name Search

Glossary

SPC	Summary of Product Characteristics (UK)

Click for further information on drug naming conventions and International Nonproprietary Names.

Silegon

Silegon may be available in the countries listed below.

Ingredient matches for Silegon

Silibinin

Silibinin is reported as an ingredient of Silegon in the following countries:

• Hungary

International Drug Name Search

Dexaminor

Dexaminor may be available in the countries listed below.

Ingredient matches for Dexaminor

Dexamethasone

Dexamethasone is reported as an ingredient of Dexaminor in the following countries:

• Brazil

International Drug Name Search