Desvenlafaxine
Encyclopedia
Desvenlafaxine also known as O-desmethylvenlafaxine, is an antidepressant
of the serotonin-norepinephrine reuptake inhibitor
class developed and marketed by Wyeth
(now part of Pfizer
). Desvenlafaxine is a synthetic
form of the major active metabolite
of venlafaxine
(sold under the brand names Effexor and Efexor). It is being targeted as the first non-hormonal based treatment for menopause
.
for desvenlafaxine. Final approval to sell the drug was contingent on a number of things, including:
The FDA approved the drug for antidepressant use in February 2008, and was to be available in US pharmacies in May 2008.
approved use of desvenlafaxine for treatment of depression in Canada. Pristiq is now available in Canadian pharmacies.
The Withdrawal Assessment Report, which summarizes the data submitted by the applicant and the opinion of the reviewing agency further noted, at page 19, that
The Benefit Risk Assessment section of the Withdrawal Assessment Report begins at p. 26 by noting that
Furthermore,
Similarly, a parallel application for approval of another desvenalfaxine succinate product as a treatment for vasomotor symptoms associated with menopause ("hot flashes") was withdrawn by Wyeth under similar circumstances in 2008. The proposed product contained the same active compound at the same dose as "Ellefore" but this application was for "Pristiq".
The Committee for Medicinal Products for Human Use found, that
Complete reporting from the European Medicines Agency regarding the withdrawal of Wyeth's application for Ellefore, including multiple language versions of the Q and A document, is freely available for public review.
Complete reporting from the European Medicines Agency regarding the withdrawal of Wyeth's application for Pristiqs, including the Withdrawal Assessment Report as well as multiple language versions of the Q and A document, is also freely available for public review.
, and is categorized as a serotonin-norepinephrine reuptake inhibitor
(SNRI). It works by blocking the transporter "reuptake" proteins
for key neurotransmitter
s affecting mood, thereby leaving more active neurotransmitters in the synapse
. The neurotransmitters affected are serotonin
(5-hydroxytryptamine) and norepinephrine
(noradrenaline). It is approximately 10 times more potent at inhibiting serotonin
uptake than norepinephrine
uptake.
When most normal metabolizers take venlafaxine - 70% of the benefit comes from venlafaxine being metabolized into desvenlafaxine so the effects are very similar. Desvenlafaxine is related to the atypical opioids Tramadol
(Ultram) and Tapentadol
(Nucynta).
being the most profound and prevalent. Although rates varied substantially from study to study, nausea was consistently the most common complaint (30-50% vs placebo
9-11%) and the most common reason for discontinuation. Suicidal ideation was monitored and was determined to be significant in 1-2 patients in each study. The most commonly observed adverse reactions in Pristiq-treated MDD patients in short-term fixed-dose studies (incidence ≥ 5% and at least twice the rate of placebo in the 50 or 100 mg dose groups) were nausea, dizziness
, insomnia
, hyperhidrosis
, constipation
, somnolence
, decreased appetite
, priapism
, night terror
s, anxiety
, and delayed ejaculation
. These side-effect patterns are consistent with those of other SNRIs venlafaxine
(Effexor) and duloxetine
(Cymbalta, Yentreve). Relative rates are not available, as there were no head-to-head studies.
Wyeth Pharmaceuticals also reports the following as potential side effects: headache
, sweating
, diarrhea
, hypertension
, abnormal bleeding and/or bruising, glaucoma
, increased cholesterol
and triglyceride
levels, low sodium
levels in the blood, and seizures.
Increases in blood pressure along with small increases in heart rate were noted in clinical trials of Pristiq, so patients with pre-existing blood pressure problems or cardiovascular diseases should always make sure that their doctor is aware of prior heart or blood pressure conditions. Blood pressure should be regularly checked in those taking Pristiq.
Although Pristiq did not increase mental or physical impairment in individuals consuming normal amounts of alcohol in a clinical study, it is generally a good idea to avoid alcohol consumption while taking Pristiq.
Pristiq has also been implicated with higher rates of discontinuation syndrome than are seen with other SSRI and SNRI antidepressant medications due to its relatively short half-life. Discontinuation syndrome side effects can be so severe as to be described as "intolerable" by former users, with some individuals unable to cease use due to extremely long-term withdrawal symptoms following cessation of use. Discontinuation symptoms can include dizziness, nausea, headache, irritability, insomnia, anxiety, fatigue, diarrhea, abnormal dreams, hyperhydrosis and paresthesia (described as "electric shock" sensations).
This drug carries the following FDA Black Box Label:
Response scores were secondary measures which the studies may or may not have been powered to address. These trials showed dose-erratic reductions in HAM-D17 scores, reductions which undermined the results. Response rates varied from 43-60%, lower than most current antidepressants, which have a 60-70% response rate. Remission rates of 23-37% for desvenlafaxine are also lower than those of other antidepressants, which have rates of 30-40%. Of course, generalizations of this nature cannot be made without careful statistical testing, and such testing was beyond the scope of this project.
Treatment duration for the three reviewed trials seemed inadequate, given the staging of Major Depressive Disorder (MDD). MDD acute phase lasts 12 weeks, while all three reviewed studies treated patients for only 8 weeks. Although it may not be practical or required to conduct a study of continuing therapy for an entire year, without the data that would result it is difficult to determine whether or not desvenlafaxine is an appropriate therapy.
and Hispanics
than the other two active groups. The only other study which listed ethnic distributions had a notably higher proportion of blacks and Hispanics in the placebo group vs. the active group. Although kinetic studies have indicated there are no known active metabolites for desvenlafaxine, the possibility of ethnic variations in response cannot be ruled out. This statement on ethnic backgrounds is solely based on an interpretation of the medication's package insert.
Antidepressant
An antidepressant is a psychiatric medication used to alleviate mood disorders, such as major depression and dysthymia and anxiety disorders such as social anxiety disorder. According to Gelder, Mayou &*Geddes people with a depressive illness will experience a therapeutic effect to their mood;...
of the serotonin-norepinephrine reuptake inhibitor
Serotonin-norepinephrine reuptake inhibitor
Serotonin–norepinephrine reuptake inhibitors are a class of antidepressant drugs used in the treatment of major depression and other mood disorders...
class developed and marketed by Wyeth
Wyeth
Wyeth, formerly one of the companies owned by American Home Products Corporation , was a pharmaceutical company. The company was based in Madison, New Jersey, USA...
(now part of Pfizer
Pfizer
Pfizer, Inc. is an American multinational pharmaceutical corporation. The company is based in New York City, New York with its research headquarters in Groton, Connecticut, United States...
). Desvenlafaxine is a synthetic
Chemical synthesis
In chemistry, chemical synthesis is purposeful execution of chemical reactions to get a product, or several products. This happens by physical and chemical manipulations usually involving one or more reactions...
form of the major active metabolite
Metabolite
Metabolites are the intermediates and products of metabolism. The term metabolite is usually restricted to small molecules. A primary metabolite is directly involved in normal growth, development, and reproduction. Alcohol is an example of a primary metabolite produced in large-scale by industrial...
of venlafaxine
Venlafaxine
Venlafaxine is an antidepressant of the serotonin-norepinephrine reuptake inhibitor class. First introduced by Wyeth in 1993, now marketed by Pfizer, it is licensed for the treatment of major depressive disorder , as a treatment for generalized anxiety disorder, and comorbid indications in...
(sold under the brand names Effexor and Efexor). It is being targeted as the first non-hormonal based treatment for menopause
Menopause
Menopause is a term used to describe the permanent cessation of the primary functions of the human ovaries: the ripening and release of ova and the release of hormones that cause both the creation of the uterine lining and the subsequent shedding of the uterine lining...
.
United States
Wyeth announced on 23 January 2007 that it received an "approvable" letter from the Food and Drug AdministrationFood and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
for desvenlafaxine. Final approval to sell the drug was contingent on a number of things, including:
- a satisfactory FDA inspection of Wyeth's Guayama, Puerto RicoGuayama, Puerto RicoGuayama is a municipality of Puerto Rico founded on January 29, 1736 and located on the Southern Coastal Valley region, bordering the Caribbean, south of Cayey; east of Salinas; and west of Patillas and Arroyo. Guayama is spread over 9 wards and Guayama Pueblo...
facility, where the drug is to be manufactured; - several post-marketing commitments;
- clarity by Wyeth around the company's product education plan for physicians and patients;
- approval of desvenlafaxine's proprietary name, Pristiq.
The FDA approved the drug for antidepressant use in February 2008, and was to be available in US pharmacies in May 2008.
Canada
On February 4, 2009, Health CanadaHealth Canada
Health Canada is the department of the government of Canada with responsibility for national public health.The current Minister of Health is Leona Aglukkaq, a Conservative Member of Parliament appointed to the position by Prime Minister Stephen Harper.-Branches, regions and agencies:Health Canada...
approved use of desvenlafaxine for treatment of depression in Canada. Pristiq is now available in Canadian pharmacies.
European Union
In the European Union desvenlafaxine succinate has not been approved for any indication. In 2008, Wyeth withdrew its application for Ellefore, the product under review for treatment of major depressive disorder. The reasons given by Wyeth, and comments regarding the findings of the reviewing agency are provided in a "question and answer" format document. The European Medicines Agency explained that
the [Committee for Medicinal Products for Human Use] had some concerns and was of the provisional opinion that Ellefore could not have been approved for the treatment of major depressive disorder [and] overall, the effectiveness of Ellefore had not been shown convincingly. In relation to its parent substance, venlafaxine, desvenlafaxine seemed to be less effective with no advantages in terms of safety and tolerability. Id.
The Withdrawal Assessment Report, which summarizes the data submitted by the applicant and the opinion of the reviewing agency further noted, at page 19, that
It is curious that the results of all flexible dose studies show a small and non-significant difference from placebo. One would expect the flexible dose studies to produce more positive results, because doses are suited to individual needs rather than being forced, as they are, in the fixed dose studies. Furthermore, flexible dose study mirror to a greater extent the
clinical situation. The applicant attributes the failure of the flexible dose studies to the high proportion of failed studies that is usually seen in depression studies but does not address the systematic nature of the difference in study results between the fixed and the flexible dose studies.Id.
The Benefit Risk Assessment section of the Withdrawal Assessment Report begins at p. 26 by noting that
"Desvenlafaxine is the main metabolite of venlafaxine. As venlafaxine is already approved for the treatment of [Major Depressive Disorder] and as venlafaxine is almost entirely transformed into desvenlafaxine, it would be expected that efficacy and safety of desvenlafaxine in the treatment of MDD would be very similar to that of venlafaxine. Id."
Furthermore,
"Efficacy of desvenlafaxine would be expected based on the fact that venlafaxine is an antidepressant with established efficacy and the fact that desvenlafaxine is the active metabolite of venlafaxine. However the efficacy results are far from impressive. The evidence with respect to long-term efficacy is considered lacking. The dose used in the randomised withdrawal study does not support long-term efficacy in the doses that are indicated in the SPC (50 mg). In addition, the definition of relapse that was used in the long-term study allows for relapses that might be due to deteriorations that are not related to depression. Therefore, the data of the long-term study need to be re-analysed with an acceptable definition of relapse."Id.
Similarly, a parallel application for approval of another desvenalfaxine succinate product as a treatment for vasomotor symptoms associated with menopause ("hot flashes") was withdrawn by Wyeth under similar circumstances in 2008. The proposed product contained the same active compound at the same dose as "Ellefore" but this application was for "Pristiq".
The Committee for Medicinal Products for Human Use found, that
"meaningful benefit of Pristiqs had not been demonstrated, when considered alongside the safety of the medicine in postmenopausal women, including side effects after stopping treatment."
Complete reporting from the European Medicines Agency regarding the withdrawal of Wyeth's application for Ellefore, including multiple language versions of the Q and A document, is freely available for public review.
Complete reporting from the European Medicines Agency regarding the withdrawal of Wyeth's application for Pristiqs, including the Withdrawal Assessment Report as well as multiple language versions of the Q and A document, is also freely available for public review.
Pharmacology
Desvenlafaxine is a synthetic form of the isolated major active metabolite of venlafaxineVenlafaxine
Venlafaxine is an antidepressant of the serotonin-norepinephrine reuptake inhibitor class. First introduced by Wyeth in 1993, now marketed by Pfizer, it is licensed for the treatment of major depressive disorder , as a treatment for generalized anxiety disorder, and comorbid indications in...
, and is categorized as a serotonin-norepinephrine reuptake inhibitor
Serotonin-norepinephrine reuptake inhibitor
Serotonin–norepinephrine reuptake inhibitors are a class of antidepressant drugs used in the treatment of major depression and other mood disorders...
(SNRI). It works by blocking the transporter "reuptake" proteins
Monoamine transporter
Monoamine transporters are protein structures that function as integral plasma membrane transporters to regulate concentrations of extracellular monoamine neurotransmitters. Three major classes of MATs are responsible for the reuptake of their associated amine neurotransmitters...
for key neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
s affecting mood, thereby leaving more active neurotransmitters in the synapse
Synapse
In the nervous system, a synapse is a structure that permits a neuron to pass an electrical or chemical signal to another cell...
. The neurotransmitters affected are serotonin
Serotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
(5-hydroxytryptamine) and norepinephrine
Norepinephrine
Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
(noradrenaline). It is approximately 10 times more potent at inhibiting serotonin
Serotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
uptake than norepinephrine
Norepinephrine
Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
uptake.
When most normal metabolizers take venlafaxine - 70% of the benefit comes from venlafaxine being metabolized into desvenlafaxine so the effects are very similar. Desvenlafaxine is related to the atypical opioids Tramadol
Tramadol
Tramadol hydrochloride is a centrally acting synthetic opioid analgesic used in treating moderate pain. The drug has a wide range of applications, including treatment for restless legs syndrome and fibromyalgia...
(Ultram) and Tapentadol
Tapentadol
Tapentadol is a centrally acting analgesic with a dual mode of action as an agonist at the μ-opioid receptor and as a norepinephrine reuptake inhibitor. While its analgesic actions have been compared to tramadol and oxycodone, its general potency is somewhere between tramadol and morphine in...
(Nucynta).
Side effects
Side-effect profiles were consistent for all three studies evaluated, with nauseaNausea
Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
being the most profound and prevalent. Although rates varied substantially from study to study, nausea was consistently the most common complaint (30-50% vs placebo
Placebo
A placebo is a simulated or otherwise medically ineffectual treatment for a disease or other medical condition intended to deceive the recipient...
9-11%) and the most common reason for discontinuation. Suicidal ideation was monitored and was determined to be significant in 1-2 patients in each study. The most commonly observed adverse reactions in Pristiq-treated MDD patients in short-term fixed-dose studies (incidence ≥ 5% and at least twice the rate of placebo in the 50 or 100 mg dose groups) were nausea, dizziness
Dizziness
Dizziness refers to an impairment in spatial perception and stability. The term is somewhat imprecise. It can be used to mean vertigo, presyncope, disequilibrium, or a non-specific feeling such as giddiness or foolishness....
, insomnia
Insomnia
Insomnia is most often defined by an individual's report of sleeping difficulties. While the term is sometimes used in sleep literature to describe a disorder demonstrated by polysomnographic evidence of disturbed sleep, insomnia is often defined as a positive response to either of two questions:...
, hyperhidrosis
Hyperhidrosis
Hyperhidrosis is the condition characterized by abnormally increased perspiration, in excess of that required for regulation of body temperature.-Classification:Hyperhidrosis can either be generalized or localized to specific parts of the body...
, constipation
Constipation
Constipation refers to bowel movements that are infrequent or hard to pass. Constipation is a common cause of painful defecation...
, somnolence
Somnolence
Somnolence is a state of near-sleep, a strong desire for sleep, or sleeping for unusually long periods . It has two distinct meanings, referring both to the usual state preceding falling asleep, and the chronic condition referring to being in that state independent of a circadian rhythm...
, decreased appetite
Appetite
The appetite is the desire to eat food, felt as hunger. Appetite exists in all higher life-forms, and serves to regulate adequate energy intake to maintain metabolic needs. It is regulated by a close interplay between the digestive tract, adipose tissue and the brain. Decreased desire to eat is...
, priapism
Priapism
Priapism is a potentially harmful and painful medical condition in which the erect penis or clitoris does not return to its flaccid state, despite the absence of both physical and psychological stimulation, within four hours. There are two types of priapism: low-flow and high-flow. Low-flow...
, night terror
Night terror
A night terror, also known as a sleep terror, incubus attack, or pavor nocturnus, is a parasomnia disorder that predominantly affects children, causing feelings of terror or dread, typically occur in the first few hours of sleep during stage 3 or 4 NREM sleep...
s, anxiety
Anxiety
Anxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
, and delayed ejaculation
Delayed ejaculation
Delayed ejaculation is the inability to ejaculate or persistent difficulty in achieving orgasm despite the presence of normal sexual desire and sexual stimulation...
. These side-effect patterns are consistent with those of other SNRIs venlafaxine
Venlafaxine
Venlafaxine is an antidepressant of the serotonin-norepinephrine reuptake inhibitor class. First introduced by Wyeth in 1993, now marketed by Pfizer, it is licensed for the treatment of major depressive disorder , as a treatment for generalized anxiety disorder, and comorbid indications in...
(Effexor) and duloxetine
Duloxetine
Duloxetine is a serotonin-norepinephrine reuptake inhibitor manufactured and marketed by Eli Lilly. It is effective for major depressive disorder and has been shown to be as effective as venlafaxine for generalized anxiety disorder...
(Cymbalta, Yentreve). Relative rates are not available, as there were no head-to-head studies.
Wyeth Pharmaceuticals also reports the following as potential side effects: headache
Headache
A headache or cephalalgia is pain anywhere in the region of the head or neck. It can be a symptom of a number of different conditions of the head and neck. The brain tissue itself is not sensitive to pain because it lacks pain receptors. Rather, the pain is caused by disturbance of the...
, sweating
Sweating
Perspiration is the production of a fluid consisting primarily of water as well as various dissolved solids , that is excreted by the sweat glands in the skin of mammals...
, diarrhea
Diarrhea
Diarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...
, hypertension
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
, abnormal bleeding and/or bruising, glaucoma
Glaucoma
Glaucoma is an eye disorder in which the optic nerve suffers damage, permanently damaging vision in the affected eye and progressing to complete blindness if untreated. It is often, but not always, associated with increased pressure of the fluid in the eye...
, increased cholesterol
Cholesterol
Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...
and triglyceride
Triglyceride
A triglyceride is an ester derived from glycerol and three fatty acids. There are many triglycerides, depending on the oil source, some are highly unsaturated, some less so....
levels, low sodium
Sodium
Sodium is a chemical element with the symbol Na and atomic number 11. It is a soft, silvery-white, highly reactive metal and is a member of the alkali metals; its only stable isotope is 23Na. It is an abundant element that exists in numerous minerals, most commonly as sodium chloride...
levels in the blood, and seizures.
Increases in blood pressure along with small increases in heart rate were noted in clinical trials of Pristiq, so patients with pre-existing blood pressure problems or cardiovascular diseases should always make sure that their doctor is aware of prior heart or blood pressure conditions. Blood pressure should be regularly checked in those taking Pristiq.
Although Pristiq did not increase mental or physical impairment in individuals consuming normal amounts of alcohol in a clinical study, it is generally a good idea to avoid alcohol consumption while taking Pristiq.
Pristiq has also been implicated with higher rates of discontinuation syndrome than are seen with other SSRI and SNRI antidepressant medications due to its relatively short half-life. Discontinuation syndrome side effects can be so severe as to be described as "intolerable" by former users, with some individuals unable to cease use due to extremely long-term withdrawal symptoms following cessation of use. Discontinuation symptoms can include dizziness, nausea, headache, irritability, insomnia, anxiety, fatigue, diarrhea, abnormal dreams, hyperhydrosis and paresthesia (described as "electric shock" sensations).
This drug carries the following FDA Black Box Label:
- WARNING: SUICIDALITY AND ANTIDEPRESSANT DRUGS
- Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of Major Depressive Disorder (MDD) and other psychiatric disorders. Anyone considering the use of PRISTIQ® or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. PRISTIQ is not approved for use in pediatric patients.
Clinical efficacy
Internal validity
In published phase 3 trials, desvenlafaxine was compared only to placebo. In these trials, primary endpoints were powered to measure a reduction in depression (HAM-D17) scores and not the standard response measure of ≥50% reduction in depression scores.Response scores were secondary measures which the studies may or may not have been powered to address. These trials showed dose-erratic reductions in HAM-D17 scores, reductions which undermined the results. Response rates varied from 43-60%, lower than most current antidepressants, which have a 60-70% response rate. Remission rates of 23-37% for desvenlafaxine are also lower than those of other antidepressants, which have rates of 30-40%. Of course, generalizations of this nature cannot be made without careful statistical testing, and such testing was beyond the scope of this project.
Treatment duration for the three reviewed trials seemed inadequate, given the staging of Major Depressive Disorder (MDD). MDD acute phase lasts 12 weeks, while all three reviewed studies treated patients for only 8 weeks. Although it may not be practical or required to conduct a study of continuing therapy for an entire year, without the data that would result it is difficult to determine whether or not desvenlafaxine is an appropriate therapy.
External validity
There may be some differences in efficacy across ethnic backgrounds. One study, with three different dose strengths, showed efficacy in the 100mg and 400mg doses, but no efficacy in the 200mg dose. This group had a notably higher proportion of blacksBlack people
The term black people is used in systems of racial classification for humans of a dark skinned phenotype, relative to other racial groups.Different societies apply different criteria regarding who is classified as "black", and often social variables such as class, socio-economic status also plays a...
and Hispanics
Hispanic and Latino Americans
Hispanic or Latino Americans are Americans with origins in the Hispanic countries of Latin America or in Spain, and in general all persons in the United States who self-identify as Hispanic or Latino.1990 Census of Population and Housing: A self-designated classification for people whose origins...
than the other two active groups. The only other study which listed ethnic distributions had a notably higher proportion of blacks and Hispanics in the placebo group vs. the active group. Although kinetic studies have indicated there are no known active metabolites for desvenlafaxine, the possibility of ethnic variations in response cannot be ruled out. This statement on ethnic backgrounds is solely based on an interpretation of the medication's package insert.