You are here: Home > Prescription(RX) Drugs > V > Vivitrol (Alkermes, Inc.)|
VIVITROL® (naltrexone for extended-release injectable suspension) is supplied as a microsphere formulation of naltrexone for suspension, to be administered by intramuscular injection. Naltrexone is an opioid antagonist with little, if any, opioid agonist activity.
Naltrexone is designated chemically as morphinan-6-one, 17-(cyclopropylmethyl)-4,5-epoxy-3,14-dihydroxy-(5α) (CAS Registry # 16590-41-3). The molecular formula is C20H23NO4 and its molecular weight is 341.41 in the anhydrous form (i.e., < 1% maximum water content). The structural formula is:
Naltrexone base anhydrous is an off-white to a light tan powder with a melting point of 168-170º C (334-338º F). It is insoluble in water and is soluble in ethanol.
VIVITROL is provided as a carton containing a vial each of VIVITROL microspheres and diluent, one 5-mL syringe, one ½-inch 20-gauge preparation needle, and two 1½-inch 20-gauge administration needles with safety device.
VIVITROL microspheres consist of a sterile, off-white to light tan powder that is available in a dosage strength of 380-mg naltrexone per vial. Naltrexone is incorporated in 75:25 polylactide-co-glycolide (PLG) at a concentration of 337 mg of naltrexone per gram of microspheres.
The diluent is a clear, colorless solution. The composition of the diluent includes carboxymethylcellulose sodium salt, polysorbate 20, sodium chloride, and water for injection. The microspheres must be suspended in the diluent prior to injection.
Mechanism of Action
Naltrexone is an opioid antagonist with highest affinity for the mu opioid receptor. Naltrexone has few, if any, intrinsic actions besides its opioid blocking properties. However, it does produce some pupillary constriction, by an unknown mechanism.
The administration of VIVITROL is not associated with the development of tolerance or dependence. In subjects physically dependent on opioids, VIVITROL will precipitate withdrawal symptomatology.
Occupation of opioid receptors by naltrexone may block the effects of endogenous opioid peptides. The neurobiological mechanisms responsible for the reduction in alcohol consumption observed in alcohol-dependent patients treated with naltrexone are not entirely understood. However, involvement of the endogenous opioid system is suggested by preclinical data.
Naltrexone blocks the effects of opioids by competitive binding at opioid receptors. This makes the blockade produced potentially surmountable, but overcoming full naltrexone blockade by administration of opioids may result in non-opioid receptor-mediated symptoms such as histamine release.
VIVITROL is not aversive therapy and does not cause a disulfiram-like reaction either as a result of opiate use or ethanol ingestion.
VIVITROL is an extended-release, microsphere formulation of naltrexone designed to be administered by intramuscular (IM) gluteal injection every 4 weeks or once a month. After IM injection, the naltrexone plasma concentration time profile is characterized by a transient initial peak, which occurs approximately 2 hours after injection, followed by a second peak observed approximately 2 - 3 days later. Beginning approximately 14 days after dosing, concentrations slowly decline, with measurable levels for greater than 1 month.
Maximum plasma concentration (Cmax) and area under the curve (AUC) for naltrexone and 6β-naltrexol (the major metabolite) following VIVITROL administration are dose proportional. Compared to daily oral dosing with naltrexone 50 mg over 28 days, total naltrexone exposure is 3 to 4-fold higher following administration of a single dose of VIVITROL 380 mg. Steady state is reached at the end of the dosing interval following the first injection. There is minimal accumulation (<15%) of naltrexone or 6β-naltrexol upon repeat administration of VIVITROL.
Naltrexone is extensively metabolized in humans. Production of the primary metabolite, 6β-naltrexol, is mediated by dihydrodiol dehydrogenase, a cytosolic family of enzymes. The cytochrome P450 system is not involved in naltrexone metabolism. Two other minor metabolites are 2-hydroxy-3-methoxy-6β-naltrexol and 2-hydroxy-3-methoxy-naltrexone. Naltrexone and its metabolites are also conjugated to form glucuronide products.
Significantly less 6β-naltrexol is generated following IM administration of VIVITROL compared to administration of oral naltrexone due to a reduction in first-pass hepatic metabolism.
Elimination of naltrexone and its metabolites occurs primarily via urine, with minimal excretion of unchanged naltrexone.
The elimination half life of naltrexone following VIVITROL administration is 5 to 10 days and is dependent on the erosion of the polymer. The elimination half life of 6β-naltrexol following VIVITROL administration is 5 to 10 days.
Hepatic Impairment: The pharmacokinetics of VIVITROL are not altered in subjects with mild to moderate hepatic impairment (Groups A and B of the Child-Pugh classification). Dose adjustment is not required in subjects with mild or moderate hepatic impairment. VIVITROL pharmacokinetics were not evaluated in subjects with severe hepatic impairment (see PRECAUTIONS).
Renal Impairment: A population pharmacokinetic analysis indicated mild renal insufficiency (creatinine clearance of 50-80 mL/min) had little or no influence on VIVITROL pharmacokinetics and that no dosage adjustment is necessary (see PRECAUTIONS). VIVITROL pharmacokinetics have not been evaluated in subjects with moderate and severe renal insufficiency (see PRECAUTIONS).
Gender: In a study in healthy subjects (n=18 females and 18 males), gender did not influence the pharmacokinetics of VIVITROL.
Age: The pharmacokinetics of VIVITROL have not been evaluated in the geriatric population.
Race: The effect of race on the pharmacokinetics of VIVITROL has not been studied.
Pediatrics: The pharmacokinetics of VIVITROL have not been evaluated in a pediatric population.
Clinical drug interaction studies with VIVITROL have not been performed.
Naltrexone antagonizes the effects of opioid-containing medicines, such as cough and cold remedies, antidiarrheal preparations and opioid analgesics (see PRECAUTIONS).
The efficacy of VIVITROL in the treatment of alcohol dependence was evaluated in a 24-week, placebo-controlled, multi-center, double-blind, randomized trial of alcohol dependent (DSM-IV criteria) outpatients. Subjects were treated with an injection every 4 weeks of VIVITROL 190 mg, VIVITROL 380 mg or placebo. Oral naltrexone was not administered prior to the initial or subsequent injections of study medication. Psychosocial support was provided to all subjects in addition to medication.
Subjects treated with VIVITROL 380 mg demonstrated a greater reduction in days of heavy drinking than those treated with placebo. Heavy drinking was defined as self-report of 5 or more standard drinks consumed on a given day for male patients and 4 or more drinks for female patients. Among the subset of patients (n=53, 8% of the total study population) who abstained completely from drinking during the week prior to the first dose of medication, compared with placebo-treated patients, those treated with VIVITROL 380 mg had greater reductions in the number of drinking days and the number of heavy drinking days. In this subset, patients treated with VIVITROL were also more likely than placebo-treated patients to maintain complete abstinence throughout treatment. The same treatment effects were not evident among the subset of patients (n=571, 92% of the total study population) who were actively drinking at the time of treatment initiation.
INDICATIONS AND USAGE:
VIVITROL is indicated for the treatment of alcohol dependence in patients who are able to abstain from alcohol in an outpatient setting prior to initiation of treatment with VIVITROL.
Patients should not be actively drinking at the time of initial VIVITROL administration.
Treatment with VIVITROL should be part of a comprehensive management program that includes psychosocial support.
VIVITROL is contraindicated in:
Naltrexone has the capacity to cause hepatocellular injury when given in excessive doses.
Naltrexone is contraindicated in acute hepatitis or liver failure, and its use in patients with active liver disease must be carefully considered in light of its hepatotoxic effects.
The margin of separation between the apparently safe dose of naltrexone and the dose causing hepatic injury appears to be only five-fold or less. VIVITROL does not appear to be a hepatotoxin at the recommended doses.
Patients should be warned of the risk of hepatic injury and advised to seek medical attention if they experience symptoms of acute hepatitis. Use of VIVITROL should be discontinued in the event of symptoms and/or signs of acute hepatitis.
In clinical trials with VIVITROL, there was one diagnosed case and one suspected case of eosinophilic pneumonia. Both cases required hospitalization, and resolved after treatment with antibiotics and corticosteroids. Should a person receiving VIVITROL develop progressive dyspnea and hypoxemia, the diagnosis of eosinophilic pneumonia should be considered (see ADVERSE REACTIONS). Patients should be warned of the risk of eosinophilic pneumonia, and advised to seek medical attention should they develop symptoms of pneumonia. Clinicians should consider the possibility of eosinophilic pneumonia in patients who do not respond to antibiotics.
Unintended Precipitation of Opioid Withdrawal
To prevent occurrence of an acute abstinence syndrome (withdrawal) in patients dependent on opioids, or exacerbation of a pre-existing subclinical abstinence syndrome, patients must be opioid-free for a minimum of 7-10 days before starting VIVITROL treatment. Since the absence of an opioid drug in the urine is often not sufficient proof that a patient is opioid-free, a naloxone challenge test should be employed if the prescribing physician feels there is a risk of precipitating a withdrawal reaction following administration of VIVITROL.
Opioid Overdose Following an Attempt to Overcome Opiate Blockade
VIVITROL is not indicated for the purpose of opioid blockade or the treatment of opiate dependence. Although VIVITROL is a potent antagonist with a prolonged pharmacological effect, the blockade produced by VIVITROL is surmountable. This poses a potential risk to individuals who attempt, on their own, to overcome the blockade by administering large amounts of exogenous opioids. Indeed, any attempt by a patient to overcome the antagonism by taking opioids is very dangerous and may lead to fatal overdose. Injury may arise because the plasma concentration of exogenous opioids attained immediately following their acute administration may be sufficient to overcome the competitive receptor blockade. As a consequence, the patient may be in immediate danger of suffering life-endangering opioid intoxication (e.g., respiratory arrest, circulatory collapse). Patients should be told of the serious consequences of trying to overcome the opioid blockade (see INFORMATION FOR PATIENTS).
There is also the possibility that a patient who had been treated with VIVITROL will respond to lower doses of opioids than previously used. This could result in potentially life-threatening opioid intoxication (respiratory compromise or arrest, circulatory collapse, etc.). Patients should be aware that they may be more sensitive to lower doses of opioids after VIVITROL treatment is discontinued (see INFORMATION FOR PATIENTS).
When Reversal of VIVITROL Blockade Is Required for Pain Management
In an emergency situation in patients receiving VIVITROL, a suggested plan for pain management is regional analgesia, conscious sedation with a benzodiazepine, and use of non-opioid analgesics or general anesthesia.
In a situation requiring opioid analgesia, the amount of opioid required may be greater than usual, and the resulting respiratory depression may be deeper and more prolonged.
A rapidly acting opioid analgesic which minimizes the duration of respiratory depression is preferred. The amount of analgesic administered should be titrated to the needs of the patient. Non-receptor mediated actions may occur and should be expected (e.g., facial swelling, itching, generalized erythema, or bronchoconstriction), presumably due to histamine release.
Irrespective of the drug chosen to reverse VIVITROL blockade, the patient should be monitored closely by appropriately trained personnel in a setting equipped and staffed for cardiopulmonary resuscitation.
Depression and Suicidality
In controlled clinical trials of VIVITROL, adverse events of a suicidal nature (suicidal ideation, suicide attempts, completed suicides) were infrequent overall, but were more common in patients treated with VIVITROL than in patients treated with placebo (1% vs. 0). In some cases, the suicidal thoughts or behavior occurred after study discontinuation, but were in the context of an episode of depression which began while the patient was on study drug. Two completed suicides occurred, both involving patients treated with VIVITROL.
Depression-related events associated with premature discontinuation of study drug were also more common in patients treated with VIVITROL (~1%) than in placebo-treated patients (0).
In the 24-week, placebo-controlled pivotal trial, adverse events involving depressed mood were reported by 10% of patients treated with VIVITROL 380 mg, as compared to 5% of patients treated with placebo injections.
Alcohol dependent patients, including those taking VIVITROL, should be monitored for the development of depression or suicidal thinking. Families and caregivers of patients being treated with VIVITROL should be alerted to the need to monitor patients for the emergence of symptoms of depression or suicidality, and to report such symptoms to the patient’s healthcare provider.
Injection Site Reactions
VIVITROL injections may be followed by pain, tenderness, induration, swelling, erythema or pruritus. In the clinical trials, one patient developed an area of induration that continued to enlarge after 4 weeks, with subsequent development of necrotic tissue that required surgical excision. Additional cases of injection site reaction with features including abscess, sterile abscess, induration, and necrosis, some of which resulted in surgical intervention, have been reported during postmarketing surveillance. Patients should be informed that any concerning injection site reactions should be brought to the attention of the physician (see INFORMATION FOR PATIENTS).
VIVITROL pharmacokinetics have not been evaluated in subjects with moderate and severe renal insufficiency. Because naltrexone and its primary metabolite are excreted primarily in the urine, caution is recommended in administering VIVITROL to patients with moderate to severe renal impairment.
Information for Patients
Physicians should discuss the following issues with patients for whom they prescribe VIVITROL:
Patients taking VIVITROL may not benefit from opioid-containing medicines (see PRECAUTIONS, Pain Management).
Because naltrexone is not a substrate for CYP drug metabolizing enzymes, inducers or inhibitors of these enzymes are unlikely to change the clearance of VIVITROL. No clinical drug interaction studies have been performed with VIVITROL to evaluate drug interactions, therefore prescribers should weigh the risks and benefits of concomitant drug use.
The safety profile of patients treated with VIVITROL concomitantly with antidepressants was similar to that of patients taking VIVITROL without antidepressants.
Carcinogenesis, mutagenesis, impairment of fertility
Carcinogenicity studies have not been conducted with VIVITROL.
Carcinogenicity studies of oral naltrexone hydrochloride (administered via the diet) have been conducted in rats and mice. In rats, there were small increases in the numbers of testicular mesotheliomas in males and tumors of vascular origin in males and females. The clinical significance of these findings is not known.
Naltrexone was negative in the following in vitro genotoxicity studies: bacterial reverse mutation assay (Ames test), the heritable translocation assay, CHO cell sister chromatid exchange assay, and the mouse lymphoma gene mutation assay. Naltrexone was also negative in an in vivo mouse micronucleus assay. In contrast, naltrexone tested positive in the following assays: Drosophila recessive lethal frequency assay, non-specific DNA damage in repair tests with E. coli and WI-38 cells, and urinalysis for methylated histidine residues.
Naltrexone given orally caused a significant increase in pseudopregnancy and a decrease in pregnancy rates in rats at 100 mg/kg/day (600 mg/m2/day). There was no effect on male fertility at this dose level. The relevance of these observations to human fertility is not known.
Pregnancy Category C
Reproduction and developmental studies have not been conducted for VIVITROL. Studies with naltrexone administered via the oral route have been conducted in pregnant rats and rabbits.
Teratogenic Effects: Oral naltrexone has been shown to increase the incidence of early fetal loss in rats administered ≥ 30 mg/kg/day (180 mg/m2/day) and rabbits administered ≥ 60 mg/kg/day (720 mg/m2/day).
There are no adequate and well-controlled studies of either naltrexone or VIVITROL in pregnant women. VIVITROL should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Labor and Delivery
The potential effect of VIVITROL on duration of labor and delivery in humans is unknown.
Transfer of naltrexone and 6β-naltrexol into human milk has been reported with oral naltrexone. Because of the potential for tumorigenicity shown for naltrexone in animal studies, and because of the potential for serious adverse reactions in nursing infants from VIVITROL, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
The safety and efficacy of VIVITROL have not been established in the pediatric population.
In trials of alcohol dependent subjects, 2.6% (n=26) of subjects were >65 years of age, and one patient was >75 years of age. Clinical studies of VIVITROL did not include sufficient numbers of subjects age 65 and over to determine whether they respond differently from younger subjects.
In all controlled and uncontrolled trials during the premarketing development of VIVITROL, more than 900 patients with alcohol and/or opioid dependence have been treated with VIVITROL. Approximately 400 patients have been treated for 6 months or more, and 230 for 1 year or longer.
Adverse Events Leading to Discontinuation of Treatment
In controlled trials of 6 months or less, 9% of patients treated with VIVITROL discontinued treatment due to an adverse event, as compared to 7% of the patients treated with placebo. Adverse events in the VIVITROL 380-mg group that led to more dropouts were injection site reactions (3%), nausea (2%), pregnancy (1%), headache (1%), and suicide-related events (0.3%). In the placebo group, 1% of patients withdrew due to injection site reactions, and 0% of patients withdrew due to the other adverse events.
Common Adverse Events
The table lists all adverse events, regardless of causality, occurring in ≥5% of patients with alcohol dependence, for which the incidence was greater in the combined VIVITROL group than in the placebo group. A majority of patients treated with VIVITROL in clinical studies had adverse events with a maximum intensity of “mild” or “moderate.”
Reports From Other Intramuscular Drug Products Containing Polylactide-co-glycolide (PLG) Microspheres – Not With VIVITROL
Retinal Artery Occlusion
Retinal artery occlusion after injection with another drug product containing polylactide-co-glycolide (PLG) microspheres has been reported very rarely during post-marketing surveillance. This event has been reported in the presence of abnormal arteriovenous anastomosis. No cases of retinal artery occlusion have been reported during VIVITROL clinical trials or post-marketing surveillance. VIVITROL should be administered by intramuscular (IM) injection into the gluteal muscle, and care must be taken to avoid inadvertent injection into a blood vessel (see DOSAGE AND ADMINISTRATION).
1 Includes the preferred terms: diarrhea NOS; frequent bowel movements; gastrointestinal upset; loose stools
2 Includes the preferred terms: abdominal pain NOS; abdominal pain upper; stomach discomfort; abdominal pain lower
3 Includes the preferred terms: upper respiratory tract infection NOS; laryngitis NOS; sinusitis NOS
4 Includes the preferred terms: nasopharyngitis; pharyngitis streptococcal; pharyngitis NOS
5 Includes the preferred terms: anxiety NEC; anxiety aggravated; agitation; obsessive compulsive disorder; panic attack; nervousness; post-traumatic stress
6 Includes the preferred terms: malaise; fatigue (these two comprise the majority of cases); lethargy; sluggishness
7 Includes the preferred terms: muscle cramps; spasms; tightness; twitching; stiffness; rigidity
8 Includes the preferred terms: rash NOS; rash papular; heat rash
9 Includes the preferred terms: headache NOS; sinus headache; migraine; frequent headaches
In clinical trials, subjects on VIVITROL had increases in eosinophil counts relative to subjects on placebo. With continued use of VIVITROL, eosinophil counts returned to normal over a period of several months.
VIVITROL 380-mg was associated with a decrease in platelet count. Patients treated with high dose VIVITROL experienced a mean maximal decrease in platelet count of 17.8 x 103/µL, compared to 2.6 x 103/µL in placebo patients. In randomized controlled trials, VIVITROL was not associated with an increase in bleeding related adverse events.
In short-term, controlled trials, the incidence of AST elevations associated with VIVITROL treatment was similar to that observed with oral naltrexone treatment (1.5% each) and slightly higher than observed with placebo treatment (0.9%).
In short-term controlled trials, more patients treated with Vivitrol 380 mg (11%) and oral naltrexone (17%) shifted from normal creatinine phosphokinase (CPK) levels before treatment to abnormal CPK levels at the end of the trials, compared to placebo patients (8%). In open-label trials, 16% of patients dosed for more than 6 months had increases in CPK. For both the oral naltrexone and Vivitrol 380-mg groups, CPK abnormalities were most frequently in the range of 1-2 x ULN. However, there were reports of CPK abnormalities as high as 4x ULN for the oral naltrexone group, and 35 x ULN for the Vivitrol 380-mg group. Overall, there were no differences between the placebo and naltrexone (oral or injectable) groups with respect to the proportions of patients with a CPK value at least three times the upper limit of normal. No factors other than naltrexone exposure were associated with the CPK elevations.
VIVITROL may be cross-reactive with certain immunoassay methods for the detection of drugs of abuse (specifically opioids) in urine. For further information, reference to the specific immunoassay instructions is recommended.
Other Events Observed During the Premarketing Evaluation of VIVITROL
The following is a list of preferred terms that reflect events reported by alcohol and/or opiate dependent subjects treated with VIVITROL in controlled trials. The listing does not include those events already listed in the previous tables or elsewhere in labeling, those events for which a drug cause was remote, those events which were so general as to be uninformative, and those events reported only once which did not have a substantial probability of being acutely life-threatening.
Gastrointestinal Disorders – constipation, toothache, flatulence, gastroesophageal reflux disease, hemorrhoids, colitis, gastrointestinal hemorrhage, paralytic ileus, perirectal abscess
Infections and Infestations – influenza, bronchitis, urinary tract infection, gastroenteritis, tooth abscess, pneumonia, cellulitis
General Disorders and Administration Site Conditions – pyrexia, lethargy, rigors, chest pain, chest tightness, weight decreased
Psychiatric Disorders – irritability, libido decreased, abnormal dreams, alcohol withdrawal syndrome, agitation, euphoric mood, delirium
Nervous System Disorders – dysgeusia, disturbance in attention, migraine, mental impairment, convulsions, ischemic stroke, cerebral arterial aneurysm
Musculoskeletal and Connective Tissue Disorders – pain in limb, muscle spasms, joint stiffness
Skin and Subcutaneous Tissue Disorders – sweating increased, night sweats, pruritus
Respiratory, Thoracic, and Mediastinal Disorders – pharyngolaryngeal pain, dyspnea, sinus congestion, chronic obstructive airways disease
Metabolism and Nutrition Disorders – appetite increased, heat exhaustion, dehydration, hypercholesterolemia
Vascular Disorders – hypertension, hot flushes, deep venous thrombosis, pulmonary embolism
Eye Disorders – conjunctivitis
Blood and Lymphatic System Disorders – lymphadenopathy (including cervical adenitis), white blood cell count increased
Cardiac Disorders – palpitations, atrial fibrillation, myocardial infarction, angina pectoris, angina unstable, cardiac failure congestive, coronary artery atherosclerosis
Immune System Disorders – seasonal allergy, hypersensitivity reaction (including angioneurotic edema and urticaria)
Pregnancy, Puerperium, and Perinatal Conditions – abortion missed
Hepatobiliary Disorders – cholelithiasis, aspartate aminotransferase increased, alanine aminotransferase increased, cholecystitis acute
DRUG ABUSE AND DEPENDENCE:
There is limited experience with overdose of VIVITROL. Single doses up to 784 mg were administered to 5 healthy subjects. There were no serious or severe adverse events. The most common effects were injection site reactions, nausea, abdominal pain, somnolence, and dizziness. There were no significant increases in hepatic enzymes.
In the event of an overdose, appropriate supportive treatment should be initiated.
DOSAGE AND ADMINISTRATION:
VIVITROL must be administered by a health care professional.
The recommended dose of VIVITROL is 380 mg delivered intramuscularly every 4 weeks or once a month. The injection should be administered by a health care professional as an intramuscular (IM) gluteal injection, alternating buttocks, using the carton components provided (see HOW SUPPLIED). VIVITROL must not be administered intravenously.
If a patient misses a dose, he/she should be instructed to receive the next dose as soon as possible.
Pretreatment with oral naltrexone is not required before using VIVITROL.
Reinitiation of Treatment in Patients Previously Discontinued
There are no data to specifically address reinitiation of treatment.
Switching From Oral Naltrexone for Alcohol Dependence
There are no systematically collected data that specifically address the switch from oral naltrexone to VIVITROL.
Preparation of Dose
VIVITROL must be suspended only in the diluent supplied in the carton and must be administered with the needle supplied in the carton. All components (i.e., the microspheres, diluent, preparation needle, and an administration needle with safety device) are required for administration. A spare administration needle is provided in case of clogging. Do not substitute any other components for the components of the carton.
VIVITROL (naltrexone for extended-release injectable suspension) is supplied in single use cartons. Each carton contains one 380 mg vial of VIVITROL microspheres, one vial containing 4 mL (to deliver 3.4 mL) Diluent for the suspension of VIVITROL, one 5-mL prepackaged syringe, one 20-gauge ½-inch needle, and two 20-gauge 1½-inch needles with safety device: NDC 63459-300-42.
Storage and Handling
The entire dose pack should be stored in the refrigerator (2 - 8ºC, 36 - 46ºF). Unrefrigerated, VIVITROL can be stored at temperatures not exceeding 25ºC (77ºF) for no more than 7 days prior to administration. Do not expose the product to temperatures above 25ºC (77ºF). VIVITROL should not be frozen.
Parenteral products should be visually inspected for particulate matter and discoloration prior to administration whenever solution and container permit. A properly mixed suspension will be milky white, will not contain clumps, and will move freely down the wall of the vial.
VIVITROL PATIENT PACKAGE INSERT (PPI)
Revised: 01/2008 Alkermes, Inc.
Reproduced with permission of U.S. National Library of Medicine
Copyright © 2018
|Over-the-counter (OTC) Drugs|