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Drug List:

Taxol

paclitaxel

Dosage Form: injection, solution
Taxol® (paclitaxel) INJECTION

(Patient Information Included)

Warning

Taxol® (paclitaxel) should be administered under the supervision of a physician experienced in the use of cancer chemotherapeutic agents. Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are readily available.

Anaphylaxis and severe hypersensitivity reactions characterized by dyspnea and hypotension requiring treatment, angioedema, and generalized urticaria have occurred in 2 to 4% of patients receiving Taxol in clinical trials. Fatal reactions have occurred in patients despite premedication. All patients should be pretreated with corticosteroids, diphenhydramine, and H2 antagonists. (See DOSAGE AND ADMINISTRATION.) Patients who experience severe hypersensitivity reactions to Taxol should not be rechallenged with the drug.

Taxol therapy should not be given to patients with solid tumors who have baseline neutrophil counts of less than 1500 cells/mm3 and should not be given to patients with AIDS-related Kaposi’s sarcoma if the baseline neutrophil count is less than 1000 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving Taxol.

Taxol Description

Taxol (paclitaxel) Injection is a clear, colorless to slightly yellow viscous solution. It is supplied as a nonaqueous solution intended for dilution with a suitable parenteral fluid prior to intravenous infusion. Taxol is available in 30 mg (5 mL), 100 mg (16.7 mL), and 300 mg (50 mL) multidose vials. Each mL of sterile nonpyrogenic solution contains 6 mg paclitaxel, 527 mg of purified Cremophor® EL* (polyoxyethylated castor oil) and 49.7% (v/v) dehydrated alcohol, USP.

*Cremophor® EL is the registered trademark of BASF Aktiengesellschaft.

Cremophor® EL is further purified by a Bristol-Myers Squibb Company proprietary process before use.

Paclitaxel is a natural product with antitumor activity. Taxol (paclitaxel) is obtained via a semi-synthetic process from Taxus baccata. The chemical name for paclitaxel is 5β,20-Epoxy-1,2α,4,7β,10β,13α-hexahydroxytax-11-en-9-one 4,10-diacetate 2-benzoate 13-ester with (2R,3S)-N-benzoyl-3-phenylisoserine.

Paclitaxel has the following structural formula:

Paclitaxel is a white to off-white crystalline powder with the empirical formula C47H51NO14 and a molecular weight of 853.9. It is highly lipophilic, insoluble in water, and melts at around 216–217° C.

Taxol - Clinical Pharmacology

Paclitaxel is a novel antimicrotubule agent that promotes the assembly of microtubules from tubulin dimers and stabilizes microtubules by preventing depolymerization. This stability results in the inhibition of the normal dynamic reorganization of the microtubule network that is essential for vital interphase and mitotic cellular functions. In addition, paclitaxel induces abnormal arrays or “bundles” of microtubules throughout the cell cycle and multiple asters of microtubules during mitosis.

Following intravenous administration of Taxol, paclitaxel plasma concentrations declined in a biphasic manner. The initial rapid decline represents distribution to the peripheral compartment and elimination of the drug. The later phase is due, in part, to a relatively slow efflux of paclitaxel from the peripheral compartment.

Pharmacokinetic parameters of paclitaxel following 3- and 24-hour infusions of Taxol at dose levels of 135 and 175 mg/m2 were determined in a Phase 3 randomized study in ovarian cancer patients and are summarized in the following table.

TABLE 1

Cmax=Maximum plasma concentration
AUC(0-∞)=Area under the plasma concentration-time curve from time 0 to infinity
CLT=Total body clearance
SUMMARY OF PHARMACOKINETIC PARAMETERS—MEAN VALUES
Dose (mg/m2)	Infusion Duration (h)	N (patients)	Cmax (ng/mL)	AUC(0-∞) (ng•h/mL)	T-HALF (h)	CLT (L/h/m2)
135	24	2	195	6300	52.7	21.7
175	24	4	365	7993	15.7	23.8
135	3	7	2170	7952	13.1	17.7
175	3	5	3650	15007	20.2	12.2

It appeared that with the 24-hour infusion of Taxol, a 30% increase in dose (135 mg/m2 vs 175 mg/m2) increased the Cmax by 87%, whereas the AUC(0-∞) remained proportional. However, with a 3-hour infusion, for a 30% increase in dose, the Cmax and AUC(0-∞) were increased by 68% and 89%, respectively. The mean apparent volume of distribution at steady state, with the 24-hour infusion of Taxol, ranged from 227 to 688 L/m2, indicating extensive extravascular distribution and/or tissue binding of paclitaxel.

The pharmacokinetics of paclitaxel were also evaluated in adult cancer patients who received single doses of 15 to 135 mg/m2 given by 1-hour infusions (n=15), 30 to 275 mg/m2 given by 6-hour infusions (n=36), and 200 to 275 mg/m2 given by 24-hour infusions (n=54) in Phase 1 and 2 studies. Values for CLT and volume of distribution were consistent with the findings in the Phase 3 study. The pharmacokinetics of Taxol in patients with AIDS-related Kaposi’s sarcoma have not been studied.

In vitro studies of binding to human serum proteins, using paclitaxel concentrations ranging from 0.1 to 50 µg/mL, indicate that between 89 to 98% of drug is bound; the presence of cimetidine, ranitidine, dexamethasone, or diphenhydramine did not affect protein binding of paclitaxel.

After intravenous administration of 15 to 275 mg/m2 doses of Taxol as 1-, 6-, or 24-hour infusions, mean values for cumulative urinary recovery of unchanged drug ranged from 1.3% to 12.6% of the dose, indicating extensive non-renal clearance. In 5 patients administered a 225 or 250 mg/m2 dose of radiolabeled Taxol as a 3-hour infusion, a mean of 71% of the radioactivity was excreted in the feces in 120 hours, and 14% was recovered in the urine. Total recovery of radioactivity ranged from 56% to 101% of the dose. Paclitaxel represented a mean of 5% of the administered radioactivity recovered in the feces, while metabolites, primarily 6α-hydroxypaclitaxel, accounted for the balance. In vitro studies with human liver microsomes and tissue slices showed that paclitaxel was metabolized primarily to 6α-hydroxypaclitaxel by the cytochrome P450 isozyme CYP2C8; and to 2 minor metabolites, 3′-p-hydroxypaclitaxel and 6α, 3′-p-dihydroxypaclitaxel, by CYP3A4. In vitro, the metabolism of paclitaxel to 6α-hydroxypaclitaxel was inhibited by a number of agents (ketoconazole, verapamil, diazepam, quinidine, dexamethasone, cyclosporin, teniposide, etoposide, and vincristine), but the concentrations used exceeded those found in vivo following normal therapeutic doses. Testosterone, 17α-ethinyl estradiol, retinoic acid, and quercetin, a specific inhibitor of CYP2C8, also inhibited the formation of 6α-hydroxypaclitaxel in vitro. The pharmacokinetics of paclitaxel may also be altered in vivo as a result of interactions with compounds that are substrates, inducers, or inhibitors of CYP2C8 and/or CYP3A4. (See PRECAUTIONS: Drug Interactions.)

The disposition and toxicity of paclitaxel 3-hour infusion were evaluated in 35 patients with varying degrees of hepatic function. Relative to patients with normal bilirubin, plasma paclitaxel exposure in patients with abnormal serum bilirubin ≤2 times upper limit of normal (ULN) administered 175 mg/m2 was increased, but with no apparent increase in the frequency or severity of toxicity. In 5 patients with serum total bilirubin >2 times ULN, there was a statistically nonsignificant higher incidence of severe myelosuppression, even at a reduced dose (110 mg/m2), but no observed increase in plasma exposure. (See PRECAUTIONS: Hepatic and DOSAGE AND ADMINISTRATION.) The effect of renal dysfunction on the disposition of paclitaxel has not been investigated.

Possible interactions of paclitaxel with concomitantly administered medications have not been formally investigated.

Clinical Studies

Ovarian Carcinoma

First-Line Data

The safety and efficacy of Taxol followed by cisplatin in patients with advanced ovarian cancer and no prior chemotherapy were evaluated in 2, Phase 3 multicenter, randomized, controlled trials. In an Intergroup study led by the European Organization for Research and Treatment of Cancer involving the Scandinavian Group NOCOVA, the National Cancer Institute of Canada, and the Scottish Group, 680 patients with Stage IIB–C, III, or IV disease (optimally or non-optimally debulked) received either Taxol 175 mg/m2 infused over 3 hours followed by cisplatin 75 mg/m2 (Tc) or cyclophosphamide 750 mg/m2 followed by cisplatin 75 mg/m2 (Cc) for a median of 6 courses. Although the protocol allowed further therapy, only 15% received both drugs for 9 or more courses. In a study conducted by the Gynecological Oncology Group (GOG), 410 patients with Stage III or IV disease (>1 cm residual disease after staging laparotomy or distant metastases) received either Taxol 135 mg/m2 infused over 24 hours followed by cisplatin 75 mg/m2 or cyclophosphamide 750 mg/m2 followed by cisplatin 75 mg/m2 for 6 courses.

In both studies, patients treated with Taxol (paclitaxel) in combination with cisplatin had significantly higher response rate, longer time to progression, and longer survival time compared with standard therapy. These differences were also significant for the subset of patients in the Intergroup study with non-optimally debulked disease, although the study was not fully powered for subset analyses (TABLES 2A and 2B). Kaplan-Meier survival curves for each study are shown in FIGURES 1 and 2.

TABLE 2A

a Taxol dose in mg/m2/infusion duration in hours; cyclophosphamide and cisplatin doses in mg/m2.
b Among patients with measurable disease only.
c Unstratified for the Intergroup Study, Stratified for Study GOG-111.
EFFICACY IN THE PHASE 3 FIRST-LINE OVARIAN CARCINOMA STUDIES
	Intergroup (non-optimally debulked subset)			GOG-111
	T175/3a c75 (n=218)		C750a c75 (n=227)	T135/24a c75 (n=196)		C750a c75 (n=214)
• Clinical Responseb	(n=153)		(n=153)	(n=113)		(n=127)
—rate (percent)	58		43	62		48
—p-valuec		0.016			0.04
• Time to Progression
—median (months)	13.2		9.9	16.6		13.0
—p-valuec		0.0060			0.0008
—hazard ratio (HR)c		0.76			0.70
—95% CIc		0.62–0.92			0.56–0.86
• Survival
—median (months)	29.5		21.9	35.5		24.2
—p-valuec		0.0057			0.0002
—hazard ratioc		0.73			0.64
—95% CIc		0.58–0.91			0.50–0.81

TABLE 2B

a Taxol dose in mg/m2/infusion duration in hours; cyclophosphamide and cisplatin doses in mg/m2.
b Among patients with measurable disease only.
c Unstratified.
EFFICACY IN THE PHASE 3 FIRST-LINE OVARIAN CARCINOMA INTERGROUP STUDY
	T175/3a c75 (n=342)		C750a c75 (n=338)
• Clinical Responseb	(n=162)		(n=161)
—rate (percent)	59		45
—p-valuec		0.014
• Time to Progression
—median (months)	15.3		11.5
—p-valuec		0.0005
—hazard ratioc		0.74
—95% CIc		0.63–0.88
• Survival
—median (months)	35.6		25.9
—p-valuec		0.0016
—hazard ratioc		0.73
—95% CIc		0.60–0.89

FIGURE 1

SURVIVAL: Cc VERSUS Tc (INTERGROUP)

FIGURE 2

SURVIVAL: Cc VERSUS Tc (GOG-111)

The adverse event profile for patients receiving Taxol in combination with cisplatin in these studies was qualitatively consistent with that seen for the pooled analysis of data from 812 patients treated with single-agent Taxol in 10 clinical studies. These adverse events and adverse events from the Phase 3 first-line ovarian carcinoma studies are described in the ADVERSE REACTIONS section in tabular (TABLES 10 and 11) and narrative form.

Second-Line Data

Data from 5, Phase 1 and 2 clinical studies (189 patients), a multicenter randomized Phase 3 study (407 patients), as well as an interim analysis of data from more than 300 patients enrolled in a treatment referral center program were used in support of the use of Taxol in patients who have failed initial or subsequent chemotherapy for metastatic carcinoma of the ovary. Two of the Phase 2 studies (92 patients) utilized an initial dose of 135 to 170 mg/m2 in most patients (>90%) administered over 24 hours by continuous infusion. Response rates in these 2 studies were 22% (95% CI,11–37%) and 30% (95% CI, 18–46%) with a total of 6 complete and 18 partial responses in 92 patients. The median duration of overall response in these 2 studies measured from the first day of treatment was 7.2 months (range, 3.5–15.8 months) and 7.5 months (range, 5.3–17.4 months), respectively. The median survival was 8.1 months (range, 0.2–36.7 months) and 15.9 months (range, 1.8–34.5+ months).

The Phase 3 study had a bifactorial design and compared the efficacy and safety of Taxol (paclitaxel), administered at 2 different doses (135 or 175 mg/m2) and schedules (3- or 24-hour infusion). The overall response rate for the 407 patients was 16.2% (95% CI, 12.8–20.2%), with 6 complete and 60 partial responses. Duration of response, measured from the first day of treatment was 8.3 months (range, 3.2–21.6 months). Median time to progression was 3.7 months (range, 0.1+ to 25.1+ months). Median survival was 11.5 months (range, 0.2 to 26.3+ months).

Response rates, median survival, and median time to progression for the 4 arms are given in the following table.

TABLE 3

EFFICACY IN THE PHASE 3 SECOND-LINE OVARIAN CARCINOMA STUDY
	175/3 (n=96)	175/24 (n=106)	135/3 (n=99)	135/24 (n=106)
• Response
—rate (percent)	14.6	21.7	15.2	13.2
—95% Confidence Interval	(8.5–23.6)	(14.5–31.0)	(9.0–24.1)	(7.7–21.5)
• Time to Progression
—median (months)	4.4	4.2	3.4	2.8
—95% Confidence Interval	(3.0–5.6)	(3.5–5.1)	(2.8–4.2)	(1.9–4.0)
• Survival
—median (months)	11.5	11.8	13.1	10.7
—95% Confidence Interval	(8.4–14.4)	(8.9–14.6)	(9.1–14.6)	(8.1–13.6)

Analyses were performed as planned by the bifactorial study design described in the protocol, by comparing the 2 doses (135 or 175 mg/m2) irrespective of the schedule (3 or 24 hours) and the 2 schedules irrespective of dose. Patients receiving the 175 mg/m2 dose had a response rate similar to that for those receiving the 135 mg/m2 dose: 18% versus 14% (p=0.28). No difference in response rate was detected when comparing the 3-hour with the 24-hour infusion: 15% versus 17% (p=0.50). Patients receiving the 175 mg/m2 dose of Taxol had a longer time to progression than those receiving the 135 mg/m2 dose: median 4.2 versus 3.1 months (p=0.03). The median time to progression for patients receiving the 3-hour versus the 24-hour infusion was 4.0 months versus 3.7 months, respectively. Median survival was 11.6 months in patients receiving the 175 mg/m2 dose of Taxol and 11.0 months in patients receiving the 135 mg/m2 dose (p=0.92). Median survival was 11.7 months for patients receiving the 3-hour infusion of Taxol and 11.2 months for patients receiving the 24-hour infusion (p=0.91). These statistical analyses should be viewed with caution because of the multiple comparisons made.

Taxol remained active in patients who had developed resistance to platinum-containing therapy (defined as tumor progression while on, or tumor relapse within 6 months from completion of, a platinum-containing regimen) with response rates of 14% in the Phase 3 study and 31% in the Phase 1 and 2 clinical studies.

The adverse event profile in this Phase 3 study was consistent with that seen for the pooled analysis of data from 812 patients treated in 10 clinical studies. These adverse events and adverse events from the Phase 3 second-line ovarian carcinoma study are described in the ADVERSE REACTIONS section in tabular (TABLES 10 and 12) and narrative form.

The results of this randomized study support the use of Taxol at doses of 135 to 175 mg/m2, administered by a 3-hour intravenous infusion. The same doses administered by 24-hour infusion were more toxic. However, the study had insufficient power to determine whether a particular dose and schedule produced superior efficacy.

Breast Carcinoma

Adjuvant Therapy

A Phase 3 Intergroup study (Cancer and Leukemia Group B [CALGB], Eastern Cooperative Oncology Group [ECOG], North Central Cancer Treatment Group [NCCTG], and Southwest Oncology Group [SWOG]) randomized 3170 patients with node-positive breast carcinoma to adjuvant therapy with Taxol or to no further chemotherapy following 4 courses of doxorubicin and cyclophosphamide (AC). This multicenter trial was conducted in women with histologically positive lymph nodes following either a mastectomy or segmental mastectomy and nodal dissections. The 3 x 2 factorial study was designed to assess the efficacy and safety of 3 different dose levels of doxorubicin (A) and to evaluate the effect of the addition of Taxol administered following the completion of AC therapy. After stratification for the number of positive lymph nodes (1–3, 4–9, or 10+), patients were randomized to receive cyclophosphamide at a dose of 600 mg/m2 and doxorubicin at doses of either 60 mg/m2 (on day 1), 75 mg/m2 (in 2 divided doses on days 1 and 2), or 90 mg/m2 (in 2 divided doses on days 1 and 2 with prophylactic G-CSF support and ciprofloxacin) every 3 weeks for 4 courses and either Taxol 175 mg/m2 as a 3-hour infusion every 3 weeks for 4 additional courses or no additional chemotherapy. Patients whose tumors were positive were to receive subsequent tamoxifen treatment (20 mg daily for 5 years); patients who received segmental mastectomies prior to study were to receive breast irradiation after recovery from treatment-related toxicities.

At the time of the current analysis, median follow-up was 30.1 months. Of the 2066 patients who were hormone receptor positive, 93% received tamoxifen. The primary analyses of disease-free survival and overall survival used multivariate Cox models, which included Taxol administration, doxorubicin dose, number of positive lymph nodes, tumor size, menopausal status, and estrogen receptor status as factors. Based on the model for disease-free survival, patients receiving AC followed by Taxol had a 22% reduction in the risk of disease recurrence compared to patients randomized to AC alone (Hazard Ratio [HR]=0.78, 95% CI, 0.67–0.91, p=0.0022). They also had a 26% reduction in the risk of death (HR=0.74, 95% CI, 0.60–0.92, p=0.0065). For disease-free survival and overall survival, p-values were not adjusted for interim analyses. Kaplan-Meier curves are shown in FIGURES 3 and 4. Increasing the dose of doxorubicin higher than 60 mg/m2 had no effect on either disease-free survival or overall survival.

FIGURE 3

DISEASE-FREE SURVIVAL: AC VERSUS AC+T

FIGURE 4

SURVIVAL: AC VERSUS AC+T

Subset analyses. Subsets defined by variables of known prognostic importance in adjuvant breast carcinoma were examined, including number of positive lymph nodes, tumor size, hormone receptor status, and menopausal status. Such analyses must be interpreted with care, as the most secure finding is the overall study result. In general, a reduction in hazard similar to the overall reduction was seen with Taxol (paclitaxel) for both disease-free and overall survival in all of the larger subsets with one exception; patients with receptor-positive tumors had a smaller reduction in hazard (HR=0.92) for disease-free survival with Taxol than other groups. Results of subset analyses are shown in TABLE 4.

TABLE 4

a Positive for either estrogen or progesterone receptors.
b Negative or missing for both estrogen and progesterone receptors (both missing: n=15).
SUBSET ANALYSES—ADJUVANT BREAST CARCINOMA STUDY
		Disease-Free Survival		Overall Survival
Patient Subset	No. of Patients	No. of Recurrences	Hazard Ratio (95% CI)	No. of Deaths	Hazard Ratio (95% CI)
• No. of Positive Nodes
1–3	1449	221	0.72 (0.55–0.94)	107	0.76 (0.52–1.12)
4–9	1310	274	0.78 (0.61–0.99)	148	0.66 (0.47–0.91)
10+	360	129	0.93 (0.66–1.31)	87	0.90 (0.59–1.36)
• Tumor Size (cm)
≤2	1096	153	0.79 (0.57–1.08)	67	0.73 (0.45–1.18)
>2 and ≤5	1611	358	0.79 (0.64–0.97)	201	0.74 (0.56–0.98)
>5	397	111	0.75 (0.51–1.08)	72	0.73 (0.46–1.16)
• Menopausal Status
Pre	1929	374	0.83 (0.67–1.01)	187	0.72 (0.54–0.97)
Post	1183	250	0.73 (0.57–0.93)	155	0.77 (0.56–1.06)
• Receptor Status
Positivea	2066	293	0.92 (0.73–1.16)	126	0.83 (0.59–1.18)
Negative/Unknownb	1055	331	0.68 (0.55–0.85)	216	0.71 (0.54–0.93)

These retrospective subgroup analyses suggest that the beneficial effect of Taxol (paclitaxel) is clearly established in the receptor-negative subgroup, but the benefit in receptor-positive patients is not yet clear. With respect to menopausal status, the benefit of Taxol is consistent (see TABLE 4 and FIGURES 5–8).

FIGURE 5

DISEASE-FREE SURVIVAL—RECEPTOR STATUS NEGATIVE/UNKNOWN

AC VERSUS AC+T

FIGURE 6

DISEASE-FREE SURVIVAL—RECEPTOR STATUS POSITIVE

AC VERSUS AC+T

FIGURE 7

DISEASE-FREE SURVIVAL—PREMENOPAUSAL

AC VERSUS AC+T

FIGURE 8

DISEASE-FREE SURVIVAL—POSTMENOPAUSAL

AC VERSUS AC+T

The adverse event profile for the patients who received Taxol subsequent to AC was consistent with that seen in the pooled analysis of data from 812 patients (TABLE 10) treated with single-agent Taxol in 10 clinical studies. These adverse events are described in the ADVERSE REACTIONS section in tabular (TABLES 10 and 13) and narrative form.

After Failure of Initial Chemotherapy

Data from 83 patients accrued in 3, Phase 2 open-label studies and from 471 patients enrolled in a Phase 3 randomized study were available to support the use of Taxol in patients with metastatic breast carcinoma.

Phase 2 open-label studies: Two studies were conducted in 53 patients previously treated with a maximum of 1 prior chemotherapeutic regimen. Taxol was administered in these 2 trials as a 24-hour infusion at initial doses of 250 mg/m2 (with G-CSF support) or 200 mg/m2. The response rates were 57% (95% CI, 37–75%) and 52% (95% CI, 32–72%), respectively. The third Phase 2 study was conducted in extensively pretreated patients who had failed anthracycline therapy and who had received a minimum of 2 chemotherapy regimens for the treatment of metastatic disease. The dose of Taxol was 200 mg/m2 as a 24-hour infusion with G-CSF support. Nine of 30 patients achieved a partial response, for a response rate of 30% (95% CI, 15–50%).

Phase 3 randomized study: This multicenter trial was conducted in patients previously treated with 1 or 2 regimens of chemotherapy. Patients were randomized to receive Taxol (paclitaxel) at a dose of either 175 mg/m2 or 135 mg/m2 given as a 3-hour infusion. In the 471 patients enrolled, 60% had symptomatic disease with impaired performance status at study entry, and 73% had visceral metastases. These patients had failed prior chemotherapy either in the adjuvant setting (30%), the metastatic setting (39%), or both (31%). Sixty-seven percent of the patients had been previously exposed to anthracyclines and 23% of them had disease considered resistant to this class of agents.

The overall response rate for the 454 evaluable patients was 26% (95% CI, 22–30%), with 17 complete and 99 partial responses. The median duration of response, measured from the first day of treatment, was 8.1 months (range, 3.4–18.1+ months). Overall for the 471 patients, the median time to progression was 3.5 months (range, 0.03–17.1 months). Median survival was 11.7 months (range, 0–18.9 months).

Response rates, median survival and median time to progression for the 2 arms are given in the following table.

TABLE 5

EFFICACY IN BREAST CANCER AFTER FAILURE OF INITIAL CHEMOTHERAPY OR WITHIN 6 MONTHS OF ADJUVANT CHEMOTHERAPY
	175/3 (n=235)		135/3 (n=236)
• Response
—rate (percent)	28		22
—p-value		0.135
• Time to Progression
—median (months)	4.2		3.0
—p-value		0.027
• Survival
—median (months)	11.7		10.5
—p-value		0.321

The adverse event profile of the patients who received single-agent Taxol in the Phase 3 study was consistent with that seen for the pooled analysis of data from 812 patients treated in 10 clinical studies. These adverse events and adverse events from the Phase 3 breast carcinoma study are described in the ADVERSE REACTIONS section in tabular (TABLES 10 and 14) and narrative form.

Non-Small Cell Lung Carcinoma (NSCLC)

In a Phase 3 open-label randomized study conducted by the ECOG, 599 patients were randomized to either Taxol (T) 135 mg/m2 as a 24-hour infusion in combination with cisplatin (c) 75 mg/m2, Taxol (T) 250 mg/m2 as a 24-hour infusion in combination with cisplatin (c) 75 mg/m2 with G-CSF support, or cisplatin (c) 75 mg/m2 on day 1, followed by etoposide (VP) 100 mg/m2 on days 1, 2, and 3 (control).

Response rates, median time to progression, median survival, and 1-year survival rates are given in the following table. The reported p-values have not been adjusted for multiple comparisons. There were statistically significant differences favoring each of the Taxol plus cisplatin arms for response rate and time to tumor progression. There was no statistically significant difference in survival between either Taxol plus cisplatin arm and the cisplatin plus etoposide arm.

TABLE 6

a Etoposide (VP) 100 mg/m2 was administered IV on days 1, 2, and 3.
b Compared to cisplatin/etoposide.
EFFICACY PARAMETERS IN THE PHASE 3 FIRST-LINE NSCLC STUDY
	T135/24 c75 (n=198)	T250/24 c75 (n=201)	VP100a c75 (n=200)
• Response
—rate (percent)	25	23	12
—p-valueb	0.001	<0.001
• Time to Progression
—median (months)	4.3	4.9	2.7
—p-valueb	0.05	0.004
• Survival
—median (months)	9.3	10.0	7.4
—p-valueb	0.12	0.08
• 1-Year Survival
—percent of patients	36	40	32

In the ECOG study, the Functional Assessment of Cancer Therapy-Lung (FACT-L) questionnaire had 7 subscales that measured subjective assessment of treatment. Of the 7, the Lung Cancer Specific Symptoms subscale favored the Taxol 135 mg/m2/24 hour plus cisplatin arm compared to the cisplatin/etoposide arm. For all other factors, there was no difference in the treatment groups.

The adverse event profile for patients who received Taxol in combination with cisplatin in this study was generally consistent with that seen for the pooled analysis of data from 812 patients treated with single-agent Taxol in 10 clinical studies. These adverse events and adverse events from the Phase 3 first-line NSCLC study are described in the ADVERSE REACTIONS section in tabular (TABLES 10 and 15) and narrative form.

AIDS-Related Kaposi’s Sarcoma

Data from 2, Phase 2 open-label studies support the use of Taxol (paclitaxel) as second-line therapy in patients with AIDS-related Kaposi’s sarcoma. Fifty-nine of the 85 patients enrolled in these studies had previously received systemic therapy, including interferon alpha (32%), DaunoXome® (31%), DOXIL® (2%), and doxorubicin containing chemotherapy (42%), with 64% having received prior anthracyclines. Eighty-five percent of the pretreated patients had progressed on, or could not tolerate, prior systemic therapy.

DaunoXome® is a registered trademark of Gilead Sciences, Inc.

DOXIL® is a registered trademark of ALZA Corporation.

In Study CA139-174, patients received Taxol at 135 mg/m2 as a 3-hour infusion every 3 weeks (intended dose intensity 45 mg/m2/week). If no dose-limiting toxicity was observed, patients were to receive 155 mg/m2 and 175 mg/m2 in subsequent courses. Hematopoietic growth factors were not to be used initially. In Study CA139-281, patients received Taxol at 100 mg/m2 as a 3-hour infusion every 2 weeks (intended dose intensity 50 mg/m2/week). In this study patients could be receiving hematopoietic growth factors before the start of Taxol therapy, or this support was to be initiated as indicated; the dose of Taxol was not increased. The dose intensity of Taxol used in this patient population was lower than the dose intensity recommended for other solid tumors.

All patients had widespread and poor-risk disease. Applying the ACTG staging criteria to patients with prior systemic therapy, 93% were poor risk for extent of disease (T1), 88% had a CD4 count <200 cells/mm3 (I1), and 97% had poor risk considering their systemic illness (S1).

All patients in Study CA139-174 had a Karnofsky performance status of 80 or 90 at baseline; in Study CA139-281, there were 26 (46%) patients with a Karnofsky performance status of 70 or worse at baseline.

TABLE 7

EXTENT OF DISEASE AT STUDY ENTRY Percent of Patients
	Prior Systemic Therapy (n=59)
Visceral ± edema ± oral ± cutaneous	42
Edema or lymph nodes ± oral ± cutaneous	41
Oral ± cutaneous	10
Cutaneous

indacaterol Inhalation

in-da-KAT-er-ol

Commonly used brand name(s)

In the U.S.

• Arcapta Neohaler

Available Dosage Forms:

• Capsule

Therapeutic Class: Bronchodilator

Pharmacologic Class: Beta-2 Adrenergic Agonist

Uses For indacaterol

Indacaterol is used to treat air flow blockage and prevent worsening of chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema. COPD is a long-term lung disease that causes bronchospasm (wheezing or difficulty with breathing).

Indacaterol is a long-acting bronchodilator. Bronchodilators are medicines that are breathed in through the mouth to open up the bronchial tubes (air passages) in the lungs. They relieve cough, wheezing, shortness of breath, and troubled breathing by increasing the flow of air through the bronchial tubes.

indacaterol is available only with your doctor's prescription.

Before Using indacaterol

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For indacaterol, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to indacaterol or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Indacaterol is not indicated for use in the pediatric population. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of indacaterol in the elderly.

Pregnancy

	Pregnancy Category	Explanation
All Trimesters	C	Animal studies have shown an adverse effect and there are no adequate studies in pregnant women OR no animal studies have been conducted and there are no adequate studies in pregnant women.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking indacaterol, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using indacaterol with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Acebutolol


• Alprenolol


• Amitriptyline


• Amoxapine


• Arotinolol


• Atenolol


• Befunolol


• Betaxolol


• Bevantolol


• Bisoprolol


• Bopindolol


• Brofaromine


• Bucindolol


• Bupranolol


• Carteolol


• Carvedilol


• Celiprolol


• Clomipramine


• Clorgyline


• Desipramine


• Dilevalol


• Dothiepin


• Doxepin


• Esmolol


• Furazolidone


• Imipramine


• Iproniazid


• Isocarboxazid


• Labetalol


• Landiolol


• Lazabemide


• Levobetaxolol


• Levobunolol


• Linezolid


• Lofepramine


• Mepindolol


• Metipranolol


• Metoprolol


• Moclobemide


• Nadolol


• Nebivolol


• Nialamide


• Nipradilol


• Nortriptyline


• Opipramol


• Oxprenolol


• Pargyline


• Penbutolol


• Phenelzine


• Pindolol


• Procarbazine


• Propranolol


• Protriptyline


• Rasagiline


• Selegiline


• Sotalol


• Talinolol


• Tertatolol


• Timolol


• Toloxatone


• Tranylcypromine


• Trimipramine

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of indacaterol. Make sure you tell your doctor if you have any other medical problems, especially:

• Allergy to milk proteins—Use with caution. indacaterol contains lactose (milk sugar) and milk proteins.

• Asthma—Do not use indacaterol if you have this condition. Some people with asthma have had more severe asthma attacks when they used indacaterol.

• COPD attack, severe—Should not be used if you are having a severe COPD attack, or if symptoms of COPD attack has already started. Your doctor may prescribe another medicine for you to use in case of an acute COPD attack.

• Diabetes or


• Heart or blood vessel disease or


• Heart rhythm problems (e.g., QT prolongation) or


• Hypertension (high blood pressure) or


• Hyperthyroidism (overactive thyroid) or


• Hypokalemia (low potassium in the blood) or


• Ketoacidosis (high ketones in the blood) or


• Seizures, history of—Use with caution. May make these conditions worse.

Proper Use of indacaterol

Use indacaterol only as directed by your doctor. Do not use more of it and do not use it more often than recommended on the label, unless otherwise directed by your doctor. Using the medicine more often may increase the chance of serious unwanted effects.

In order for indacaterol to help prevent COPD attacks, it must be used once a day at the same time each day as ordered by your doctor.

Indacaterol inhalation powder is used with a special inhaler (Neohaler™) and usually comes with a Medication Guide and patient directions. Read the directions carefully before using indacaterol. If you do not understand the directions or you are not sure how to use the inhaler, ask your doctor to show you what to do. Also, ask your doctor to check how you use the inhaler to make sure you are using it properly.

To use indacaterol inhalation powder with the Neohaler™:

• Dry your hands before handling indacaterol.


• Open a blister card of capsules. Do not remove a capsule until you are ready for a dose.


• Open the base of inhaler firmly and tilt the mouthpiece to open the inhaler.


• Place the capsule only in the capsule-chamber in the base of the inhaler. Do not swallow the capsule and do not place a capsule directly into the mouthpiece.


• Hold the mouthpiece of the inhaler upright and press both buttons at the same time. Press the buttons only once. You should hear a click as the capsule is being pierced.


• Breathe out fully. Do not exhale into the mouthpiece.


• Place the mouthpiece in your mouth then close your lips around the mouthpiece.


• Breathe in quickly and deeply.


• Remove the inhaler from your mouth. Hold your breath as long as you can and then exhale.


• Open the inhaler after using it, and remove and discard the empty capsule. Do not leave the used capsule inside the chamber.


• Close the mouthpiece and then replace the cover.


• Do not wash the inhaler. Keep it dry.


• You may reuse your inhaler. But use a new inhaler with each refill of your medicine.


• Do not use the inhaler for indacaterol with any other medicine.

Dosing

The dose of indacaterol will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of indacaterol. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For inhalation powder dosage form (used with Neohaler™):
  
  • For maintenance treatment of COPD:
    
    • Adults—75 micrograms (mcg) (1 capsule) by oral inhalation once a day.
    
    
    • Children—Use is not recommended.
    
    
  
  

Missed Dose

If you miss a dose of indacaterol, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Do not use indacaterol more than one time every 24 hours.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Precautions While Using indacaterol

If you will be using indacaterol for a long time, it is very important that your doctor check you at regular visits. This will allow your doctor to see if the medicine is working properly and to check for any unwanted effects.

Tell your doctor if you are also using other medicines for your COPD. Your doctor may want you to stop using the other medicine and use it only during a severe COPD attack. Follow your doctor's instructions on how you should take your medicine.

indacaterol should not be used if you are having a severe COPD attack, or if symptoms of COPD attack has already started. Your doctor may prescribe another medicine for you to use in case of an acute COPD attack. If the other medicine does not work as well, tell your doctor right away.

Talk to your doctor or get medical care right away:

• Your symptoms do not improve after using indacaterol within a few days or if they become worse.


• Your short-acting inhaler does not seem to be working as well as usual and you need to use it more often.

indacaterol should not be used together with similar inhaled medicines such as arformoterol (Brovana™), budesonide/formoterol (Symbicort®), formoterol (Foradil®, Perforomist™), salmeterol (Serevent®), or salmeterol/fluticasone (Advair®).

indacaterol may cause paradoxical bronchospasm, which means your breathing or wheezing will get worse. Paradoxical bronchospasm may be life-threatening. Stop using indacaterol and check with your doctor right away if you are having a cough, difficulty with breathing, shortness of breath, or wheezing after using indacaterol.

Hypokalemia (low potassium in the blood) may occur while you are using indacaterol. Check with your doctor right away if you have more than one of the following symptoms: decreased urine; dry mouth; increased thirst; loss of appetite; mood changes; muscle pain or cramps; nausea or vomiting; numbness or tingling in the hands, feet, or lips; seizures; shortness of breath; uneven heartbeat; or unusual tiredness or weakness.

indacaterol may affect blood sugar levels. If you are diabetic and notice a change in the results of your blood or urine sugar tests, check with your doctor.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

indacaterol Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

More common

• Arm, back, or jaw pain


• chest pain or discomfort


• chest tightness or heaviness


• cough


• dizziness


• fainting


• fast or irregular heartbeat


• fever or chills


• nausea


• shortness of breath


• sneezing


• sore throat


• sweating


• tightness in the chest


• troubled breathing


• wheezing

Less common

• Abdominal or stomach pain


• bloating or swelling of the face, arms, hands, lower legs, or feet


• blurred vision


• body aches or pain


• dry mouth


• ear congestion


• fainting


• flushed, dry skin


• fruit-like breath odor


• headache


• increased hunger


• increased thirst


• increased urination


• loss of consciousness


• loss of voice


• rapid weight gain


• runny or stuffy nose


• stomachache


• sweating


• tingling of the hands or feet


• unexplained weight loss


• unusual tiredness or weakness


• unusual weight gain or loss


• vomiting

Incidence not known

• Fast, irregular, pounding, or racing heartbeat or pulse

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

Less common

• Muscle or bone pain


• muscle spasm


• pain or tenderness around the eyes and cheekbones

Incidence not known

• Itching skin


• rash

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

See also: indacaterol Inhalation side effects (in more detail)

The information contained in the Thomson Reuters Micromedex products as delivered by Drugs.com is intended as an educational aid only. It is not intended as medical advice for individual conditions or treatment. It is not a substitute for a medical exam, nor does it replace the need for services provided by medical professionals. Talk to your doctor, nurse or pharmacist before taking any prescription or over the counter drugs (including any herbal medicines or supplements) or following any treatment or regimen. Only your doctor, nurse, or pharmacist can provide you with advice on what is safe and effective for you.

The use of the Thomson Reuters Healthcare products is at your sole risk. These products are provided "AS IS" and "as available" for use, without warranties of any kind, either express or implied. Thomson Reuters Healthcare and Drugs.com make no representation or warranty as to the accuracy, reliability, timeliness, usefulness or completeness of any of the information contained in the products. Additionally, THOMSON REUTERS HEALTHCARE MAKES NO REPRESENTATION OR WARRANTIES AS TO THE OPINIONS OR OTHER SERVICE OR DATA YOU MAY ACCESS, DOWNLOAD OR USE AS A RESULT OF USE OF THE THOMSON REUTERS HEALTHCARE PRODUCTS. ALL IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE OR USE ARE HEREBY EXCLUDED. Thomson Reuters Healthcare does not assume any responsibility or risk for your use of the Thomson Reuters Healthcare products.

More indacaterol Inhalation resources

• Indacaterol Inhalation Side Effects (in more detail)
• Indacaterol Inhalation Use in Pregnancy & Breastfeeding
• Indacaterol Inhalation Drug Interactions
• Indacaterol Inhalation Support Group
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• COPD, Maintenance

Valni XL 30mg & 60mg Prolonged Release Tablets

VALNI XL 30MG & 60MG PROLONGED RELEASE TABLETS

Nifedipine

Read all of this leaflet carefully before you start taking this medicine.

• Keep this leaflet. You may need to read it again.


• If you have any further questions, ask your doctor or pharmacist.


• This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.


• If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

In this leaflet:

• 1. What VALNI XL is and what it is used for


• 2. Before you take VALNI XL


• 3. How to take VALNI XL


• 4. Possible side effects


• 5. How to store VALNI XL


• 6. Further information

What Valni Xl Is And What It Is Used For

VALNI XL Prolonged Release Tablets contain nifedipine which belongs to a group of medicines called calcium-channel blockers that act on the cardiovascular system (the heart and blood vessels). VALNI XL has been prescribed by your doctor to treat your high blood pressure or to reduce the frequency of your anginal attacks. They are called prolonged release tablets because they are manufactured in a way that allows the nifedipine to be released and slowly absorbed by your body over a period of several hours.

In high blood pressure, nifedipine works by widening the blood vessels. This creates less resistance to the blood flow, and results in lower blood pressure, which in turn reduces the strain on your heart.

In angina, nifedipine works by opening up the arteries supplying the heart muscle and this allows more blood and oxygen to reach the muscle, decreasing the chances of angina (chest pains) occuring when extra strain is placed upon the heart.

Before You Take Valni Xl

Do not take VALNI XL:

• if you are allergic to nifedipine, other calcium-channel blockers (e.g verapamil, diltiazem or felodipine) or any of the other ingredients of VALNI XL


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


• if you have been told that you have a narrowing (stenosis) of the aortic valve in your heart


• if you have experienced a collapse which was caused by a heart problem (cardiogenic shock)


• if the severity or frequency of your angina has rapidly worsened over a matter of hours or days


• to treat an angina attack as it occurs, but rather to reduce the frequency of the angina you experience over time


• if you suffer from inflammation of the bowel or intestines (such as Crohn’s disease), oesophageal (gullet) obstruction or have in the past had an obstruction or narrowing of the intestine


• if you have a liver disease


• if you have had a heart attack during the last month or to treat a heart attack


• if you are taking the antibiotic rifampicin (used to treat tuberculosis)


• if your blood pressure continues to rise despite treatment (malignant hypertension)

Take special care with VALNI XL:

It is important that you tell your doctor if any of the following applies to you.

• if you suffer from low blood pressure


• if you experience chest pains when you first start taking VALNI XL, contact your doctor immediately


• if you are diabetic, the treatment for your diabetes may need to be adjusted


• if you are receiving kidney dialysis and have very high blood pressure with low blood volume


• if you are taking other drugs to treat high blood pressure (e.g. beta-blockers). If you are changing from a beta-blocker to nifedipine, you should gradually reduce your beta-blocker after discussion with your doctor


• if you have a Kock pouch (a type of ileostomy)


• if you have to give a urine sample, have an x-ray or undergo surgery

Your doctor may, under certain conditions, think it necessary to keep you on VALNI XL whilst you are pregnant. If this is the case particular care must be taken if you are also receiving magnesium sulphate injections.

Taking other medicines:

Tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.

In particular, tell your doctor if you are taking:

• other drugs to treat high blood pressure


• cimetidine, to treat stomach ulcers


• the medicines digoxin, diltiazem, quinidine, or beta-blockers, used to treat heart conditions


• the anti-epileptic drug phenytoin


• the antibiotic rifampicin and combination treatment quinupristin/dalfopristin


• cisapride, a drug used to treat reduced movements of the gullet and stomach

The effect of the following drugs on VALNI XL is uncertain. Therefore, as a additional precaution, please tell your doctor if you are taking:

• the antibiotics erythromycin, ketoconazole, itraconazole or fluconazole


• the HIV protease inhibitors indinavir, nelfinavir, ritonavir or saquinavir


• the antidepressant drugs fluoxetine and nefazodone


• tacrolimus, an immunosuppressant used to prevent the rejection of transplant organs


• carbamazepine and valproic acid, used for the treatment of epilepsy


• the barbiturate phenobarbital, used primarily to treat insomnia and anxiety

The following drugs do not interact with VALNI XL: aspirin, benazepril, candesartan cilexetil, orlistat, debrisoquine, doxazosin, irbesartan, omeprazole, pantoprazole, ranitidine, rosiglitazone and triamterene hydrochlorothiazide.

Taking VALNI XL with food and drink:

Do not drink grapefruit juice at the same time or soon after taking VALNI XL because grapefruit juice can increase the blood levels of nifedipine.

Pregnancy and breast-feeding:

Do not take VALNI XL if you are pregnant, trying to become pregnant or are breast-feeding.

Drugs like VALNI XL have been shown in laboratory experiments to impair sperm function. If you are male and have been unsuccessful in fathering a child please consult your doctor.

Ask your doctor or pharmacist for advice before taking any medicine.

Driving and using machines:

It is possible that you may react to VALNI XL. Reactions can vary in intensity from individual to individual and may affect your concentration. If you are unable to concentrate or remain alert after taking VALNI XL, then do not drive or operate machinery or perform any activity for which you need to be attentive. This applies particularly at the start of treatment, on changing medication or in combination with alcohol.

Important information about some of the ingredients of VALNI XL:

VALNI XL contains lactose monohydrate. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.

How To Take Valni Xl

Always take VALNI XL exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure.

VALNI XL is specially formulated so that you only have to take your tablets once a day, preferably in the morning. Your tablet must be swallowed whole with a glass of water and not with grapefruit juice. Do not break or chew your tablets.

The usual adult dose for treating high blood pressure or preventing angina is 30mg or 60mg once a day.

Your doctor may decide to increase your dose to a maximum of 90mg of nifedipine once a day.

If you are elderly, lower doses of this medicine may be prescribed by your doctor.

Do not stop taking your medicine until your doctor tells you.

Children must not take this medicine.

If you take more VALNI XL than you should:

If you take more VALNI XL than you should, immediately contact your doctor or pharmacist. Elimination of the product and the restoration of stable cardiovascular conditions may be needed. If you take too much nifedipine low blood pressure (hypotension) can occur, which can be recognised from symptoms like dizziness, nausea, vomiting, drowsiness, confusion, lethargy, flushing, a lack of oxygen (hypoxia), headache or red spots on the face. Eventually, unconsiousness can occur. Increased or decreased heart rates are also a symptom of overdose. In the event of overdose it is recommended to lay the patient down with elevated legs, for instance by using some pillows.

If you forget to take VALNI XL:

Do not take a double dose to make up for a forgotten dose.

If you have any further questions on the use of this product, ask your doctor or pharmacist.

If you stop taking VALNI XL:

If you suddenly stop using this medicine, the symptoms that you had before you started taking this medicine can come back.

If you have any further questions on the use of this product, ask your doctor or pharmacist.

Possible Side Effects

Like all medicines, VALNI XL can cause side effects, although not everyone gets them. If you do experience any of these effects they will usually go away when treatment is stopped.

If you experience chest pains when you first start taking VALNI XL, contact your doctor immediately.

The most common side effects that may affect 1 person in 10 are: headache, an irregular heartbeat (palpitations), flushing, general weakness or loss of strength and energy, constipation, dizziness and swelling particularly of the ankles and legs.

Less common side effects which may affect less than 1 person in 100 are: pain particularly in the stomach area (abdomen), chest and legs, general feeling of being unwell, a low blood pressure when rising to the standing position (hypotension), fainting, a fast heart beat (tachycardia), diarrhoea, a dry mouth, indigestion, wind (flatulence), feeling sick, leg cramps, sleep disorders, nervousness, pins and needles, dizziness (vertigo), difficulty in breathing, itching, rash, an increase in the need to pass water and bed wetting.

Rare side effects which may affect less than 1 person in 1,000 are: allergic reactions which may appear as a yellowing of the skin (jaundice), chills, swelling of the face, fever, problems with your circulatory system, loss of appetite (anorexia), belching, problems with your gut, inflammation of the gums, tender or swollen gums which may bleed, an increase in gamma glutamyl-transferase (an enzyme that occurs naturally in the body), liver function abnormalities, vomiting, problems with your joints that may be painful, muscle pain, increased sensitivity particularly in the skin, trembling, mood changes, nose bleeds, hives that appear on the body, lips, eyes, or tongue, sweating, problems with the eyes that may be painful or cause blurred vision, difficulty in passing water that may be painful and a failure to achieve or maintain an erection (impotence).

Very rare side effects which may affect approximately 1 person in 10,000 are: an allergic reaction that may become severe, a mass of foreign material found in the stomach which may require surgery for removal, difficulty in swallowing, inflammation of the gullet, problems with the gums, obstruction of the gut, ulcers in the gut, jaundice, an increase in serum glutamate pyruvate transaminase (an enzyme that occurs naturally in the body), a reduction in the number of white blood cells, weight loss, muscle cramps and blistering of the skin when exposed to sunlight. Too much glucose in the blood (hyperglycaemia) may also occur. Symptoms of hyperglycaemia include thirst, resulting in need to pass water more frequently, weight loss and tiredness.

A slight development in breast tissue has also been reported in older men on long term therapy.

As with similar drugs which act on blood vessels, chest (anginal) pain may occur rarely at the start of treatment with VALNI XL.

Because of the nature of coronary artery disease, heart attacks have occurred in patients treated with the active ingredient, nifedipine. It has not been shown that these heart attacks were due to treatment with nifedipine.

If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

How To Store Valni Xl

• Keep out of the reach and sight of children.


• Do not store above 25°C. Keep the blister in the outer carton.


• Do not use VALNI XL after the expiry date which is stated on the blister and carton.


• Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help protect the environment.

Further Information.

What VALNI XL contains:

• The active substance is nifedipine.


• The other ingredients are povidone K30, lactose monohydrate, talc, hypromellose (E464), magnesium stearate, carbomer 974P, colloidal anhydrous silica, macrogol 4000, dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate copolymer, red iron oxide (E172) and titanium dioixide (E171).

What VALNI XL look like and the contents of the pack:

Valni XL 30mg and 60 mg Prolonged Release Tablets are pale red with a round and biconvex shape, marked on one side with “30” or “60” respectively. They are available in calendar blister packs of 28 tablets.

Marketing Authorisation Holder and Manufacturer.

Marketing Authorisation Holder:

Winthrop Pharmaceuticals

PO Box 611

Guildford

Surrey

GU1 4YS

Manufacturer:

Chester Medical Solutions

3-4 Apex Court

Bassendale Road

Bromborough

Wirral

CH62 3RE

This leaflet was last revised in October 2007

'Winthrop' is a registered trademark. © 2007 Winthrop Pharmaceuticals.

LF00000019

Xibrom

Generic Name: Bromfenac Sodium
Class: Nonsteroidal Anti-inflammatory Agents
VA Class: CN104
Chemical Name: 2-amino-3-(4-bromobenzoyl)benzeneacetic acid sesquihydrate monosodium salt
Molecular Formula: C₁₅H₁₁BrNNaO₃
CAS Number: 120638-55-3

Introduction

Prototypical NSAIA.¹

Uses for Xibrom

Postoperative Ocular Inflammation and Pain

Management of ocular inflammation and pain associated with cataract extraction.¹

Xibrom Dosage and Administration

Administration

Ophthalmic Administration

Apply topically to the eye as an ophthalmic solution.¹

Avoid contamination of the solution container.²

Do not administer while wearing contact lenses.¹ (See Advice to Patients.)

Dosage

Available as bromfenac sodium sesquihydrate; dosage expressed in terms of bromfenac.¹

Adults

Postoperative Ocular Inflammation and Pain

Ophthalmic

1 drop of a 0.09% solution in the affected eye(s) twice daily, beginning 24 hours after cataract surgery and continuing through the first 2 weeks of the postoperative period.¹

Cautions for Xibrom

Contraindications

• 
  

  Known hypersensitivity to bromfenac sodium or any ingredient in the formulation.¹

  
  

Warnings/Precautions

Warnings

Bleeding

May inhibit platelet aggregation and prolong bleeding time.¹

May cause increased bleeding of ocular tissues (including hyphemas) when used in conjunction with ocular surgery.¹

Use with caution in patients with underlying bleeding tendencies or in those receiving drugs known to prolong bleeding time.¹

Sensitivity Reactions

Hypersensitivity Reactions

Possible cross-sensitivity with aspirin, phenylacetic acid derivatives, and other NSAIAs.¹ Use with caution in patients with history of hypersensitivity to these drugs.¹

Sulfite Sensitivity

Formulation contains sodium sulfite, which may cause allergic-type reactions (including anaphylaxis and life-threatening or less severe asthmatic episodes) in certain susceptible individuals.¹

General Precautions

Wound-healing Complications

May slow or delay wound healing.¹ (See Specific Drugs under Interactions.)

Ocular Effects

Use may result in keratitis.¹ In some susceptible patients, continued use may result in epithelial breakdown, corneal thinning, corneal erosion, corneal ulceration, or corneal perforation; these events may be sight-threatening.¹ If manifestations of corneal epithelial breakdown occur, discontinue therapy immediately and monitor for corneal health.¹

Patients with complicated ocular surgeries, corneal denervation, corneal epithelial defects, diabetes mellitus, ocular surface diseases (e.g., dry eye syndrome), rheumatoid arthritis, or repeat ocular surgeries within a short period of time may be at increased risk for developing adverse corneal effects that may become sight-threatening.¹ Use with caution in these patients.¹

Use >24 hours prior to surgery or use beyond 14 days postoperatively may precipitate or exacerbate adverse corneal effects.¹

Specific Populations

Pregnancy

Category C.¹

Avoid use in late pregnancy (i.e., third trimester) because of known effects on the fetal cardiovascular system (possible premature closure of the ductus arteriosus).^{1 2}

Lactation

Not known whether distributed into milk following ophthalmic administration.² Use with caution.¹

Pediatric Use

Safety and efficacy not established in children <18 years of age.¹

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults.¹

Common Adverse Effects

Abnormal ocular sensation, conjunctival hyperemia, ocular redness or irritation (e.g., pruritus, burning, stinging, pain), headache, iritis.¹

Interactions for Xibrom

No formal drug interaction studies to date.³

Specific Drugs

Drug	Interaction	Comments
Corticosteroids, topical	Increased potential for wound-healing complications1

Xibrom Pharmacokinetics

Absorption

Bioavailability

Systemic concentration at steady state in humans estimated to be below limit of quantification (50 ng/mL).¹

Stability

Storage

Ophthalmic

Solution

15–25°C.¹

ActionsActions

• 
  

  Inhibits synthesis of prostaglandins in body tissues by inhibiting cyclooxygenase (COX), including both COX-1 and COX-2 isoenzymes.¹

  
  


• 
  

  Ocular effects associated principally with inhibition of ocular prostaglandin synthesis.^{1 2}

  
  

Advice to Patients

• 
  

  Risk of ocular bleeding.¹ Risk of anaphylactoid and other sensitivity reactions.¹

  
  


• 
  

  Importance of learning and adhering to proper administration techniques to avoid contamination of the ophthalmic solution with common bacteria that can cause ocular infections.²

  
  


• 
  

  Importance of removing contact lenses before administration.¹

  
  


• 
  

  Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹ Risk of use during late pregnancy.¹

  
  


• 
  

  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as concomitant illnesses.¹

  
  


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  Importance of informing patients of other important precautionary information.¹ (See Cautions.)

  
  

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Bromfenac Sodium

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Ophthalmic	Solution	0.09% (of bromfenac)	Xibrom (with benzalkonium chloride, povidone, and sodium sulfite)	ISTA

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions May 2006. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. ISTA Pharmaceuticals, Inc. Xibrom (bromfenac ophthalmic solution) 0.09% prescribing information. Irvine, CA; 2006 Feb.

2. ISTA Pharmaceuticals, Inc., Irvine, CA: Personal communication.

3. ISTA Pharmaceuticals, Inc. Xibrom (bromfenac ophthalmic solution 0.09%) formulary submission dossier. Irvine, CA; 2005.

More Xibrom resources

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

• Xibrom Prescribing Information (FDA)


• Xibrom Advanced Consumer (Micromedex) - Includes Dosage Information


• Xibrom MedFacts Consumer Leaflet (Wolters Kluwer)


• Xibrom Consumer Overview


• Bromday Prescribing Information (FDA)


• Bromday Consumer Overview

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