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Votrient

Side Effects
Interactions

SIDE EFFECTS

Clinical Trials Experience

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

Potentially serious adverse reactions with VOTRIENT included:

Renal Cell Carcinoma

The safet y of VOTRIENT has been evaluated in 977 patients in the monotherapy trials which included 586 patients with RCC at the time of NDA submission. With a median duration of treatment of 7.4 months (range 0.1 to 27.6), the most commonly observed adverse reactions ( ≥ 20%) in the 586 patients were diarrhea, hypertension, hair color change, nausea, fatigue, anorexia, and vomiting.

The data described below reflect the safet y profile of VOTRIENT in 290 RCC patients who participated in a randomized, double-blind, placebo-controlled trial [see Clinical Studies]. The median duration of treatment was 7.4 months (range 0 to 23) for patients who received VOTRIENT and 3.8 months (range 0 to 22) for the placebo arm. Forty-two percent of patients on VOTRIENT required a dose interruption. Thirty-six percent of patients on VOTRIENT were dose reduced. Table 1 presents the most common adverse reactions occurring in ≥ 10% of patients who received VOTRIENT.

Table 1: Adverse Reactions Occurring in ≥ 10% of Patients With RCC who Received VOTRIENT

Adverse Reactions VOTRIENT
(N = 290)
Placebo
(N = 145)
All Gradesa
%
Grade 3
%
Grade 4
%
All Gradesa
%
Grade 3
%
Grade 4
%
Diarrhea 52 3 < 1 9 < 1 0
Hypertension 40 4 0 10 < 1 0
Hair color changes 38 < 1 0 3 0 0
Nausea 26 < 1 0 9 0 0
Anorexia 22 2 0 10 < 1 0
Vomiting 21 2 < 1 8 2 0
Fatigue 19 2 0 8 1 1
Asthenia 14 3 0 8 0 0
Abdominal pain 11 2 0 1 0 0
Headache 10 0 0 5 0 0
aNational Cancer Institute Common Terminology Criteria for Adverse Events, version 3.

Other adverse reactions observed more commonly in patients treated with VOTRIENT than placebo and that occurred in < 10% (any grade) were alopecia (8% versus < 1%), chest pain (5% versus 1%), dysgeusia (altered taste) (8% versus < 1%), dyspepsia (5% versus < 1%), dysphonia (4% versus < 1%), facial edema (1% versus 0%), palmar-plantar erythrodysesthesia (hand-foot syndrome) (6% versus < 1%), proteinuria (9% versus 0%), rash (8% versus 3%), skin depigmentation (3% versus 0%), and weight decreased (9% versus 3%).

Additional adverse reactions from other clinical trials in RCC patients treated with VOTRIENT are listed below:

Musculoskeletal and Connective Tissue Disorders: Arthralgia, muscle spasms.

Table 2 presents the most common laboratory abnormalities occurring in > 10% of patients who received VOTRIENT and more commonly ( ≥ 5%) in patients who received VOTRIENT versus placebo.

Table 2: Selected Laboratory Abnormalities Occurring in > 10% of Patients With RCC who Received VOTRIENT and More Commonly ( ≥ 5%) in Patients who Received VOTRIENT Versus Placebo

Parameters VOTRIENT
(N = 290)
Placebo
(N = 145)
All Gradesa
%
Grade 3
%
Grade 4
%
All Gradesa
%
Grade 3
%
Grade 4
%
Hematologic
Leukopenia 37 0 0 6 0 0
Neutropenia 34 1 < 1 6 0 0
Thrombocytopenia 32 < 1 < 1 5 0 < 1
Lymphocytopenia 31 4 < 1 24 1 0
Chemistry
ALT increased 53 10 2 22 1 0
AST increased 53 7 < 1 19 < 1 0
Glucose increased 41 < 1 0 33 1 0
Total bilirubin increased 36 3 < 1 10 1 < 1
Phosphorus decreased 34 4 0 11 0 0
Sodium decreased 31 4 1 24 4 0
Magnesium decreased 26 < 1 1 14 0 0
Glucose decreased 17 0 < 1 3 0 0
aNational Cancer Institute Common Terminology Criteria for Adverse Events, version 3.

Soft Tissue Sarcoma

The safety of VOTRIENT has been evaluated in 382 patients with advanced soft tissue sarcoma, with a median duration of treatment of 3.6 months (range 0 to 53). The most commonly observed adverse reactions ( ≥ 20%) in the 382 patients were fatigue, diarrhea, nausea, decreased weight, hypertension, decreased appetite, vomiting, tumor pain, hair color changes, musculoskeletal pain, headache, dysgeusia, dyspnea, and skin hypopigmentation.

The data described below reflect the safety profile of VOTRIENT in 240 patients who participated in a randomized, double-blind, placebo-controlled trial [see Clinical Studies].

The median duration of treatment was 4.5 months (range 0 to 24) for patients who received VOTRIENT and 1.9 months (range 0 to 24) for the placebo arm. Fifty-eight percent of patients on VOTRIENT required a dose interruption. Thirty-eight percent of patients on VOTRIENT had their dose reduced. Seventeen percent of patients who received VOTRIENT discontinued therapy due to adverse reactions. Table 3 presents the most common adverse reactions occurring in ≥ 10% of patients who received VOTRIENT.

Table 3: Adverse Reactions Occurring in ≥ 10% of Patients With STS who Received VOTRIENT

Adverse Reactions VOTRIENT
(N = 240)
Placebo
(N = 123)
All Gradesa
%
Grade 3
%
Grade 4
%
All Gradesa
%
Grade 3
%
Grade 4
%
Fatigue 65 13 1 48 4 1
Diarrhea 59 5 0 15 1 0
Nausea 56 3 0 22 2 0
Weight decreased 48 4 0 15 0 0
Hypertension 42 7 0 6 0 0
Appetite decreased 40 6 0 19 0 0
Hair color changes 39 0 0 2 0 0
Vomiting 33 3 0 11 1 0
Tumor pain 29 8 0 21 7 2
Dysgeusia 28 0 0 3 0 0
Headache 23 1 0 8 0 0
Musculoskeletal pain 23 2 0 20 2 0
Myalgia 23 2 0 9 0 0
Gastrointestinal pain 23 3 0 9 4 0
Dyspnea 20 5 < 1 17 5 1
Exfoliative rash 18 < 1 0 9 0 0
Cough 17 < 1 0 12 < 1 0
Peripheral edema 14 2 0 9 2 0
Mucositis 12 2 0 2 0 0
Alopecia 12 0 0 1 0 0
Dizziness 11 1 0 4 0 0
Skin disorderb 11 2 0 1 0 0
Skin hypopigmentation 11 0 0 0 0 0
Stomatitis 11 < 1 0 3 0 0
Chest pain 10 2 0 6 0 0
aNational Cancer Institute Common Terminology Criteria for Adverse Events, version 3.
b27 of the 28 cases of skin disorder were palmar-plantar erythrodysesthesia.

Other adverse reactions observed more commonly in patients treated with VOTRIENT that occurred in ≥ 5% of patients and at an incidence of more than 2% difference from placebo included insomnia (9% versus 6%), hypothyroidism (8% versus 0%), dysphonia (8% versus 2%), epistaxis (8% versus 2%), left ventricular dysfunction (8% versus 4%), dyspepsia (7% versus 2%), dry skin (6% versus < 1%), chills (5% versus 1%), vision blurred (5% versus 2%), and nail disorder (5% versus 0%).

Table 4 presents the most common laboratory abnormalities occurring in > 10% of patients who received VOTRIENT and more commonly ( ≥ 5%) in patients who received VOTRIENT versus placebo.

Table 4: Selected Laboratory Abnormalities Occurring in > 10% of Patients With STS who Received VOTRIENT and More Commonly ( ≥ 5%) in Patients who Received VOTRIENT Versus Placebo

Parameters VOTRIENT
(N = 240)
Placebo
(N = 123)
All Gradesa
%
Grade 3
%
Grade 4
%
All Gradesa
%
Grade 3
%
Grade 4
%
Hematologic
  Leukopenia 44 1 0 15 0 0
  Lymphocytopenia 43 10 0 36 9 2
  Thrombocytopenia 36 3 1 6 0 0
  Neutropenia 33 4 0 7 0 0
Chemistry
  AST increased 51 5 3 22 2 0
  ALT increased 46 8 2 18 2 1
  Glucose increased 45 < 1 0 35 2 0
  Albumin decreased 34 1 0 21 0 0
  Alkaline phosphatase increased 32 3 0 23 1 0
  Sodium decreased 31 4 0 20 3 0
  Total bilirubin increased  29 1 0 7 2 0
  Potassium increased 16 1 0 11 0 0
aNational Cancer Institute Common Terminology Criteria for Adverse Events, version 3.

Diarrhea

Diarrhea occurred frequently and was predominantly mild to moderate in severity in both the RCC and STS clinical trials. Patients should be advised how to manage mild diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs so appropriate management can be implemented to minimize its impact.

Lipase Elevations

In a single-arm RCC trial, increases in lipase values were observed for 27% (48/181) of patients. Elevations in lipase as an adverse reaction were reported for 4% (10/225) of patients and were Grade 3 for 6 patients and Grade 4 for 1 patient. In the RCC trials of VOTRIENT, clinical pancreatitis was observed in < 1% (4/586) of patients.

Pneumothorax

Two of 290 patients treated with VOTRIENT and no patient on the placebo arm in the randomized RCC trial developed a pneumothorax. In the randomized trial of VOTRIENT for the treatment of STS, pneumothorax occurred in 3% (8/240) of patients treated with VOTRIENT and in no patients on the placebo arm.

Bradycardia

In the randomized trial of VOTRIENT for the treatment of RCC, bradycardia based on vital signs ( < 60 beats per minute) was observed in 19% (52/280) of patients treated with VOTRIENT and in 11% (16/144) of patients on the placebo arm. Bradycardia was reported as an adverse reaction in 2% (7/290) of patients treated with VOTRIENT compared to < 1% (1/145) of patients treated with placebo. In the randomized trial of VOTRIENT for the treatment of STS, bradycardia based on vital signs ( < 60 beats per minute) was observed in 19% (45/238) of patients treated with VOTRIENT and in 4% (5/121) of patients on the placebo arm. Bradycardia was reported as an adverse reaction in 2% (4/240) of patients treated with VOTRIENT compared to < 1% (1/123) of patients treated with placebo.

Postmarketing Experience

The following adverse reactions have been identified during post approval use of VOTRIENT. Because these reactions are reported voluntarily from a population of uncertain size it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure.

Gastrointestinal Disorders: Pancreatitis

Read the Votrient (pazopanib tablets) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

Drugs That Inhibit Or Induce Cytochrome P450 3A4 Enzymes

In vitro studies suggested that the oxidative metabolism of pazopanib in human liver microsomes is mediated primarily by CYP3A4, with minor contributions from CYP1A2 and CYP2C8. Therefore, inhibitors and inducers of CYP3A4 may alter the metabolism of pazopanib.

CYP3A4 Inhibitors

Coadministration of pazopanib with strong inhibitors of CYP3A4 (e.g., ketoconazole, ritonavir, clarithromycin) increases pazopanib concentrations and should be avoided. Consider an alternate concomitant medication with no or minimal potential to inhibit CYP3A4 [see CLINICAL PHARMACOLOGY]. If coadministration of a strong CYP3A4 inhibitor is warranted, reduce the dose of VOTRIENT to 400 mg [see DOSAGE AND ADMINISTRATION]. Grapefruit or grapefruit juice should be avoided as it inhibits CYP3A4 activity and may also increase plasma concentrations of pazopanib.

CYP3A4 Inducers

CYP3A4 inducers such as rifampin may decrease plasma pazopanib concentrations. Consider an alternate concomitant medication with no or minimal enzyme induction potential. VOTRIENT should not be used if chronic use of strong CYP3A4 inducers cannot be avoided [see DOSAGE AND ADMINISTRATION].

Drugs That Inhibit Transporters

In vitro studies suggested that pazopanib is a substrate of P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP). Therefore, absorption and subsequent elimination of pazopanib may be influenced by products that affect Pgp and BCRP.

Concomitant treatment with strong inhibitors of Pgp or breast cancer resistance protein (BCRP) should be avoided due to risk of increased exposure to pazopanib. Selection of alternative concomitant medicinal products with no or minimal potential to inhibit Pgp or BCRP should be considered.

Effects Of Pazopanib On CYP Substrates

Results from drug-drug interaction trials conducted in cancer patients suggest that pazopanib is a weak inhibitor of CYP3A4, CYP2C8, and CYP2D6 in vivo, but had no effect on CYP1A2, CYP2C9, or CYP2C19 [see CLINICAL PHARMACOLOGY].

Concomitant use of VOTRIENT with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended. Coadministration may result in inhibition of the metabolism of these products and create the potential for serious adverse events [see CLINICAL PHARMACOLOGY].

Effect Of Concomitant Use Of VOTRIENT And Simvastatin

Concomitant use of VOTRIENT and simvastatin increases the incidence of ALT elevations. Across monotherapy studies with VOTRIENT, ALT > 3 X ULN was reported in 126/895 (14%) of patients who did not use statins, compared with 11/41 (27%) of patients who had concomitant use of simvastatin. If a patient receiving concomitant simvastatin develops ALT elevations, follow dosing guidelines for VOTRIENT or consider alternatives to VOTRIENT [see WARNINGS AND PRECAUTIONS]. Alternatively, consider discontinuing simvastatin [see WARNINGS AND PRECAUTIONS]. Insufficient data are available to assess the risk of concomitant administration of alternative statins and VOTRIENT.

Drugs That Raise Gastric pH

In a drug interaction trial in patients with solid tumors, concomitant administration of pazopanib with esomeprazole, a proton pump inhibitor (PPI), decreased the exposure of pazopanib by approximately 40% (AUC and Cma x). Therefore, concomitant use of VOTRIENT with drugs that raise gastric pH should be avoided. If such drugs are needed, short-acting antacids should be considered in place of PPIs and H2 receptor antagonists. Separate antacid and pazopanib dosing by several hours to avoid a reduction in pazopanib exposure [see CLINICAL PHARMACOLOGY].

Read the Votrient Drug Interactions Center for a complete guide to possible interactions

Last reviewed on RxList: 6/16/2014
This monograph has been modified to include the generic and brand name in many instances.

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