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Promethazine


Promethazine is a derivative functioning as a first-generation with prominent , , and effects, employed to alleviate allergic reactions, , , , and to induce . Approved for use in the United States prior to 1951, it blocks H1 receptors competitively while also antagonizing muscarinic receptors and D2 receptors, contributing to its multifaceted therapeutic profile despite lacking the ring substitutions typical of phenothiazines. Administered orally, rectally, intramuscularly, or intravenously, promethazine effectively mitigates symptoms of hay fever, , and , and serves as an adjunct in care for its calming properties; however, its use has drawn scrutiny due to risks of respiratory depression—particularly fatal in children under two years—and severe tissue from inadvertent intra-arterial or perivascular injection, prompting FDA-mandated label revisions and contraindications. Empirical data underscore its efficacy in controlled settings but highlight dose-dependent adverse effects like and QT prolongation, necessitating cautious application informed by causal mechanisms rather than rote indications.

Medical Applications

Approved Indications

Promethazine hydrochloride is approved by the U.S. (FDA) for the management of allergic disorders through its H1 receptor antagonism, including perennial and seasonal , vasomotor rhinitis, due to inhalant allergens and foods, mild uncomplicated urticaria and , dermographism, amelioration of allergic reactions to or , and adjunctive in anaphylactic reactions after acute symptoms have been controlled with epinephrine and other measures. The drug is indicated as an antiemetic for the prevention and control of nausea and vomiting associated with certain types of anesthesia and surgery, as well as active and prophylactic treatment of motion sickness; these uses leverage its central antitussive and vestibular suppressant effects. Promethazine serves as a sedative for preoperative, postoperative, and obstetric settings, including during labor, to relieve apprehension and produce light sleep from which patients can be easily aroused; it is approved for both pediatric and adult use in these contexts. Additionally, it is indicated as adjunctive therapy to analgesics such as meperidine for control of postoperative pain, enhancing sedation without primary analgesic action. These indications apply across formulations including oral tablets, rectal suppositories, and injectable solutions, with dosing tailored to the route and condition; for instance, injection is approved for situations where is impractical, such as in adjunct or special surgical procedures requiring reduced doses.

Off-Label and Investigational Uses

Promethazine is employed off-label for the treatment of peripheral vertigo in settings, where intravenous has demonstrated superior symptom compared to in a double-blind randomized trial involving adults, achieving greater reductions in visual analog scale scores for vertigo (mean change 46.5 mm versus 25.7 mm) and associated at 2 hours post-infusion. Its vestibular suppressant effects also extend to acute management of and vestibular neuronitis, providing short-term symptom control alongside supportive measures, though spontaneous recovery predominates and prolonged use risks delaying vestibular compensation. Evidence from comparative studies supports antihistamines like promethazine over benzodiazepines for acute vertigo at 2 hours, but lacks long-term outcome data. In psychiatric contexts, promethazine serves off-label as a adjunct, particularly in combination with for rapid tranquilization of or induced by . A Cochrane review of randomized trials indicates that intramuscular plus promethazine achieves faster (within 30 minutes) and greater clinical improvement at 2 hours than alone, with lower risks of extrapyramidal effects due to promethazine's properties. Standalone use for psychiatric or yields limited efficacy, with observational data highlighting rebound upon discontinuation and no robust randomized evidence endorsing it over established agents, especially in populations prone to sensitivity. Off-label applications in acute management include combinations with , where a multicenter randomized double-blind trial reported significantly higher rates of pain freedom at 2 hours (promethazine plus sumatriptan versus sumatriptan alone) among patients with moderate-to-severe attacks. Prophylactic use for prevention lacks support from randomized trials, with available data confined to acute settings and potential overshadowed by side effects like . Promethazine is used off-label for , providing relief in based on clinical experience, though classified as FDA C with insufficient controlled trials to confirm safety or superiority over alternatives like . Investigational exploration includes diabetic , where a randomized placebo-controlled trial assessed oral promethazine (12.5 mg three times daily for 28 days) for symptom improvement, though results remain pending broader validation. Emerging but preliminary data suggest adjunctive roles in symptom alleviation, often via combinations addressing and anxiety; however, studies emphasize misuse risks and morbidity when co-administered with opioids, without isolated randomized evidence establishing efficacy or safety profiles. Overall, these uses highlight reliance on promethazine's multifactorial amid evidence gaps, necessitating caution against overgeneralization from small-scale or adjunctive trial designs.

Adverse Effects and Safety Concerns

Common Adverse Effects

Drowsiness and represent the most frequently reported adverse effects of promethazine, often leading to impaired mental and physical performance in clinical use and post-marketing reports. These effects typically manifest shortly after administration and may persist for several hours. Other common central nervous system effects include , , disorientation, and restlessness. manifestations, such as dry mouth, , , and or hesitancy, are routinely observed, with heightened incidence among elderly patients due to age-related physiological changes. Extrapyramidal symptoms, including and , occur in some instances during short-term therapy, as documented in adverse event surveillance.

Serious and Long-Term Risks

Promethazine carries a black-box warning from the U.S. (FDA) prohibiting its use in pediatric patients under 2 years of age due to the potential for fatal respiratory depression, with postmarketing reports documenting deaths from this effect even at approved dosages. This risk stems from promethazine's antihistaminic and properties, which can suppress central respiratory drive, particularly in young children whose immature physiology exacerbates sensitivity to such agents. As a derivative with D2 receptor antagonism, promethazine has been implicated in rare but severe cases of (NMS), characterized by , muscle rigidity, autonomic instability, and altered mental status, with multiple case reports attributing onset directly to promethazine administration. Long-term use also elevates the risk of , an irreversible involving involuntary orofacial and limb movements, though specific incidence rates for promethazine remain understudied compared to typical antipsychotics; phenothiazine-class drugs generally carry a 15-30% risk of tardive dyskinesia with prolonged exposure in vulnerable populations such as the elderly. Intravenous of promethazine poses a substantial of severe injury, including , , and , due to its vesicant properties causing chemical irrespective of inadvertent ; the FDA updated labeling in December 2023 to mandate dilution to at least 25 mg/mL, at a rate not exceeding 25 mg/min, and avoidance of small veins to mitigate these outcomes, which have necessitated surgical interventions like in reported cases. Promethazine can prolong the on electrocardiograms, increasing susceptibility to and sudden cardiac death in patients with predisposing factors such as imbalances, congenital , or concomitant use of other QT-prolonging drugs; intravenous doses have demonstrated significant QTc prolongation in controlled studies without altering transmural dispersion of repolarization, underscoring a mechanistic link via hERG blockade.

Contraindications and Special Populations

Promethazine is contraindicated in comatose patients due to the risk of exacerbated (CNS) depression. It is also contraindicated in individuals with known to promethazine or other derivatives, as idiosyncratic reactions may occur. In neonates and pediatric patients under 2 years of age, promethazine administration is contraindicated owing to documented cases of fatal respiratory depression; FDA identified 22 instances of respiratory depression in children aged 1.5 months to 2 years, including 7 fatalities, often linked to oversedation. Caution is advised in children aged 2 to 6 years, where promethazine use has been associated with and requires lowest effective dosing with close monitoring for signs of CNS depression. Elderly patients warrant special precaution, as they exhibit heightened sensitivity to promethazine's and effects, elevating fall risk and confusion; dosage reduction is recommended to mitigate these outcomes. In patients with or severe respiratory impairment, promethazine should be avoided or used judiciously, given its potential to induce or worsen respiratory depression independent of . Concomitant administration with other CNS depressants, such as opioids, alcohol, or barbiturates, amplifies sedation and respiratory risks in vulnerable populations, necessitating avoidance or dose adjustment. During pregnancy, promethazine is classified as FDA category C, with animal reproduction studies demonstrating fetal harm at high doses but limited controlled human data; use only if potential benefit justifies risk, particularly avoiding in the first trimester absent compelling need. In lactating women, promethazine passes into breast milk and may cause drowsiness or other effects in nursing infants, advising against use or discontinuation of breastfeeding. Additive anticholinergic interactions with other agents like tricyclic antidepressants further contraindicate or restrict use in populations prone to glaucoma or prostatic hypertrophy.

Overdose and Acute Toxicity

Promethazine overdose typically presents with (CNS) depression as the predominant feature, progressing from and to , , or seizures depending on the ingested dose. effects, including dry mouth, flushed skin, (dilated pupils), , and , frequently accompany these symptoms, while respiratory depression and may occur in severe cases. , characterized by agitation, hallucinations, and disorientation, is a key indicator of significant and correlates directly with the amount ingested, with risks increasing substantially above 500 mg in adults. Acute toxicity data indicate promethazine as moderately toxic, with a probable oral estimated at 0.5-5 g/kg body weight, though survival has been reported after ingestions exceeding 1 g in adults with prompt intervention. Animal studies provide contextual LD50 values, such as 255-326 mg/kg orally in mice, underscoring the narrow , particularly in vulnerable populations like children where even therapeutic doses can precipitate . Early CNS depression often dominates the clinical course, with emerging within hours of ingestion. Management of promethazine overdose emphasizes supportive measures, as no specific antidote exists; initial steps include securing the airway, providing mechanical ventilation if respiratory depression is evident, and administering activated charcoal for recent ingestions to reduce absorption. Cardiovascular monitoring is essential to address tachycardia or arrhythmias, with intravenous fluids for hypotension and benzodiazepines for agitation or seizures; physostigmine may be considered cautiously for refractory anticholinergic delirium but risks exacerbating CNS depression. Prognosis improves with early decontamination and intensive care, though fatalities have occurred from untreated respiratory failure or aspiration.

Pharmacology

Pharmacodynamics

Promethazine functions primarily as a competitive at histamine H1 receptors, blocking Gq-protein-coupled signaling pathways that mediate allergic responses, , and effects such as . This H1 underlies its antihistaminic efficacy by preventing -induced increases in intracellular calcium and subsequent cellular responses in target tissues. Secondary antagonism at D2 receptors, particularly in the of the , inhibits emetogenic signaling via Gi-protein-coupled pathways, contributing to effects independent of peripheral gastrointestinal actions. Promethazine also blocks muscarinic receptors (M1-M5 subtypes), disrupting Gq- or Gi-coupled muscarinic signaling to produce effects like reduced glandular secretions and enhanced central sedation. Antagonism of alpha-adrenergic receptors, including alpha-1 subtypes, interferes with Gq-mediated and tone, predisposing to through reduced noradrenergic . These multi-receptor interactions, with prominent H1 blockade relative to stronger D2 affinity in antipsychotic phenothiazines like , explain the predominance of and antihistaminic profiles over pronounced effects. Central nervous system penetration allows dose-dependent dominance of H1 and muscarinic antagonism over peripheral actions, amplifying at therapeutic doses via blockade of wake-promoting histaminergic and pathways in the .

Pharmacokinetics and

Promethazine is rapidly absorbed following oral , with approximately 88% of the dose absorbed from the , though absolute is reduced to about 25% due to extensive first-pass in the liver. Peak concentrations are typically reached within 1.5 to 3 hours after oral dosing. Intramuscular results in quicker compared to oral or rectal routes, with peak levels often occurring sooner, while intravenous achieves immediate systemic exposure with 100% . The drug is widely distributed throughout the body, exhibiting high of approximately 93%. varies widely, reported as 17-277 L/kg. Hepatic metabolism is the primary route of , predominantly mediated by 2D6 (), with contributions from , yielding active metabolites such as N-desmethylpromethazine and promethazine , which contribute to prolonged pharmacological effects. These metabolites undergo further conjugation, primarily and sulfoxidation. Elimination occurs mainly through renal excretion of inactive metabolites and conjugates, with lesser fecal elimination; unchanged drug in is minimal (<1%). The plasma half-life in healthy adults ranges from 9 to 16 hours following intravenous or intramuscular , potentially extending to 16-19 hours with oral dosing due to enterohepatic recirculation or variable absorption. Pharmacokinetic variability is influenced by factors including age, hepatic function, and genetic polymorphisms in . Poor metabolizers exhibit reduced clearance and prolonged exposure, increasing risk of adverse effects, while liver impairment slows metabolism and extends . and show high interindividual variability across routes, necessitating route-specific dosing adjustments.

Chemistry

Chemical Structure and Properties

Promethazine is a derivative characterized by a dibenzothiazepine core, with the central at position 10 substituted by a 1-methyl-2-(dimethylamino)ethyl , more precisely described as N,N-dimethyl-1-(10H-phenothiazin-10-yl)propan-2-amine per IUPAC . Its molecular formula is C₁₇H₂₀N₂S, and the molecular weight is 284.42 g/mol. The free base manifests as white to faint yellow crystals or a crystalline , with a of 60 °C and low of 15.6 mg/L at 24 °C; it dissolves readily in organic solvents such as and but is practically insoluble in acetone, ether, and . The salt, commonly used in formulations, exhibits high , facilitating parenteral administration. The tertiary amine in the possesses a of 9.1, rendering it protonated and ionized under acidic conditions, which enhances aqueous of the salt form and influences for . Promethazine is light-sensitive and demonstrates at lower values. In structure-activity relationships among phenothiazines, the rigid, planar tricyclic nucleus adopts a conformation mimicking dopamine's extended form, enabling competitive binding at D2 receptors and contributing to shared neuroleptic properties with congeners like ; the unbranched alkylamine at N-10 prioritizes H1 antihistaminic potency over pronounced blockade, distinguishing promethazine's profile.

Synthesis and Formulation

Promethazine is synthesized via N- of at the 10-position with 3-chloro-N,N-dimethylpropan-1-amine (also known as 1-dimethylamino-2-propyl chloride) in the presence of a base such as or , followed by acidification to form the salt. This route, developed in the 1940s by Paul Charpentier and colleagues at laboratories, yields the active compound after purification steps including and salt formation. Industrial processes often employ similar under controlled conditions to minimize side products, with subsequent concentration under reduced pressure and hydrochloride for high-purity production. Common pharmaceutical formulations include oral tablets at strengths of 12.5 mg, 25 mg, and 50 mg; at 6.25 mg per 5 mL in a flavored base with approximately 7% and 4.7–5.2; injectable solutions at 25 mg/mL or 50 mg/mL for intramuscular or intravenous use; and rectal suppositories at 12.5 mg, 25 mg, or 50 mg. These forms are designed to enhance , with oral and rectal routes providing systemic absorption suitable for and effects, while injectables allow rapid onset but require careful administration to avoid tissue damage. Promethazine demonstrates sensitivity to , with studies indicating non- influenced by , light exposure, and solution conditions; degradation products form via oxidative pathways, necessitating light-protected storage and packaging. Thermal stability is also -dependent, with activation energies varying across acidic to basic media, impacting long-term integrity in matrices like . For intravenous formulations, the FDA mandated labeling updates in December 2023 to highlight risks of severe chemical irritation and tissue damage, recommending dilution or deep over undiluted IV use to preserve while minimizing local reactions.

History and Development

Discovery and Early Research

Promethazine was synthesized in 1946 by scientists at the pharmaceutical company as an N-dimethylaminopropyl derivative of , initially designated RP 3277, in pursuit of novel compounds building on earlier analogs. This development followed preclinical screening for antagonism, with Halpern at the Centre for Scientific Research confirming its potent H1-receptor blocking activity in animal models, surpassing prior antihistamines in efficacy and duration. The compound's involved of with 1-(dimethylamino)propan-2-ol derivatives, yielding a structure optimized for central and peripheral antihistaminic effects. Early pharmacological evaluations in the late emphasized its applications beyond suppression, revealing pronounced and properties in and assays, which prompted initial human trials for and preoperative anxiolysis. By the early , controlled studies in clinics tested promethazine—branded as Phenergan—for and urticaria, documenting reduced histamine-induced wheal-and-flare responses in over 80% of participants at doses of 25 mg orally or intramuscularly. These trials also quantified its onset within 20-30 minutes, attributing it to H1 blockade in the , though with noted variability in impairment across subjects. Pre-approval investigations extended to potential, with French surgical cohorts in 1950 demonstrating promethazine's ability to halve postoperative nausea incidence compared to , via intramuscular administration of 50 mg prior to , based on empirical tracking of emetic episodes in 100+ patients. Such findings underscored its multimodal action—combining antihistaminic, , and weak antagonism—without the toxicity seen in earlier phenothiazines, paving empirical groundwork for broader therapeutic exploration.

Regulatory Approvals and Milestones

Promethazine hydrochloride was approved by the U.S. (FDA) for medical use in 1951 under the brand name Phenergan, initially for the treatment of allergic conditions such as , , and . The injectable formulation followed in 1956. In response to post-marketing reports of respiratory depression and fatalities, the FDA added a warning in 2004 contraindicating promethazine use in children under 2 years of age due to risks of severe or fatal respiratory depression. This was reinforced in 2006 with an alert emphasizing avoidance in pediatric patients under 2 years. The 2009 U.S. decision in Wyeth v. addressed promethazine's labeling adequacy following a case of arterial injection leading to ; the ruled 6-3 that FDA approval does not state-law failure-to-warn claims, enabling manufacturers to strengthen warnings without prior agency approval and prompting subsequent labeling enhancements for injection risks. In September 2009, the FDA mandated a for injectable promethazine, contraindicating and highlighting risks of severe tissue injury from inadvertent intra-arterial or perivascular . Safety concerns with promethazine-codeine combinations, particularly abuse potential and pediatric risks, led to FDA restrictions: in 2008-2009, contraindication for children under 12 years; expanded in 2017 to under 18 years for respiratory conditions due to heightened risks of slowed breathing and death. Promethazine with oral solution remains Schedule V controlled in the U.S., reflecting low abuse potential but ongoing monitoring. In December 2023, the FDA required labeling updates for promethazine hydrochloride injection, recommending deep intramuscular administration over intravenous to minimize severe tissue damage, or dilution with 10-20 mL saline if IV infusion is necessary via large veins. Internationally, promethazine received approval in various forms across Europe and elsewhere following U.S. precedents, with agencies like the EMA aligning on contraindications for young children and injection precautions based on shared pharmacovigilance data, though specific dates vary by jurisdiction.

Society, Regulation, and Controversies

Availability, Formulations, and Market Status

Promethazine hydrochloride is commercially available in form worldwide, with original brand-name products such as Phenergan introduced decades ago and patents long expired, enabling widespread generic production and distribution. Common brand names include Phenergan, Promethegan (for rectal suppositories ), and Phenadoz, alongside numerous generics manufactured by companies like Ayerst, , and Epic Pharma. The drug is formulated for oral administration as tablets (typically 12.5 mg, 25 mg, or 50 mg) or syrup, rectal suppositories (12.5 mg, 25 mg, or 50 mg), and injectable solutions (25 mg/mL or 50 mg/mL for intramuscular, intravenous, or subcutaneous use). These formulations support its applications in allergy relief, nausea control, and sedation, with generics offering lower costs compared to branded versions. Regulatory status varies by country: in the United States, promethazine requires a prescription for all indications, while in the and , certain oral formulations like Phenergan are available over-the-counter for allergies and , subject to oversight in some cases such as (Schedule 3 for oral products). Injectable forms have faced ongoing supply shortages , with promethazine injection listed as currently unavailable due to constraints as of October 2025. In market terms, promethazine remains a staple generic with steady demand; in 2023, it was the 230th most prescribed medication in the United States, exceeding 1 million prescriptions annually, though its role in nausea management has partly shifted toward alternatives like ondansetron in clinical settings.

Recreational Use and Abuse Potential

Promethazine is recreationally misused primarily in combination with codeine-containing cough syrups to produce "purple drank" or "lean," a beverage mixed with soda and often candy, sought for its euphoric and sedating effects. This practice originated in the 1990s within Southern United States hip-hop culture, particularly in Houston's rap scene, where it gained prominence through artist endorsements and lyrics glamorizing the mixture's relaxing high. The combination exploits promethazine's antihistamine-induced sedation to potentiate codeine's opioid effects, resulting in intensified respiratory depression and heightened overdose risk, with multiple fatalities linked to chronic use and polysubstance involvement. Beyond combinations, promethazine is abused standalone or with other substances for its calming and properties, particularly among individuals with dependence, patients, and adolescents, who report using it to enhance euphoria or self-medicate anxiety. pharmacovigilance data from 2010 to 2019 documented 557 adverse reaction reports of promethazine misuse, including over 95 cases among young adults (aged 18-30), with 310 total fatalities primarily attributed to drug toxicity and abuse, often in polysubstance contexts like or . , postmortem analyses have detected promethazine in 8.7% to 14.2% of -related overdose deaths, underscoring its role in exacerbating fatal outcomes through . Evidence indicates promethazine's abuse potential exceeds perceptions of it as low-risk, with rapid development to its sedating effects and symptoms upon cessation, including rebound , anxiety, , and restlessness lasting up to 6-8 weeks in users. Dependence has been observed in case reports of prolonged misuse, where users escalate doses to counteract , leading to psychiatric symptoms and heightened vulnerability to polysubstance overdoses. Illegal dispensing contributes to availability; in 2024, a was sentenced to three years in for distributing thousands of doses of promethazine cough syrup without valid prescriptions, fueling street markets known as "green drink" or "purple drink."

Regulatory Actions and Restrictions

The U.S. (FDA) contraindicates promethazine hydrochloride injection in pediatric patients under 2 years of age owing to the potential for fatal respiratory depression. A emphasizes risks of death from slowed or stopped breathing in young children, prompting recommendations for the lowest effective dose in those 2 years and older, alongside avoidance of concomitant depressants. These restrictions stem from post-marketing adverse event data linking promethazine to pediatric fatalities. For parenteral administration, the FDA mandates labeling updates requiring deep over intravenous or subcutaneous routes to prevent severe tissue injury, including and , as intravenous use has been associated with higher complication rates regardless of dilution or site. Reinforced in December 2023, these guidelines reflect evidence from clinical reports of injection-related hazards. Promethazine-codeine combinations face heightened scrutiny due to diversion and ; the FDA withdrew approval for their use in and treatments for patients under 18 years in January 2018, based on data showing disproportionate respiratory risks in youth. The () schedules such oral solutions as controlled substances under Schedule V, acknowledging low but present potential tied to codeine's effects. Internationally, controls reflect varying abuse surveillance; escalated promethazine's regulatory status in 2014 to curb misuse linked to fatalities and dependency patterns. Australia's prohibits its use in children under 6 years, citing similar safety concerns from data. reports further document promethazine's involvement in drug-related deaths, often in polydrug contexts, informing tighter prescription oversight. Supply chain disruptions have compounded access challenges; promethazine injection shortages persisted from 2023 into 2025, with manufacturers like X-Gen projecting backorder resolution no earlier than November 2025, straining clinical protocols for , , and indications. Inclusion on the U.S. Pharmacopeia's 2024-2025 vulnerable medicines list underscores systemic vulnerabilities exacerbating these regulatory-enforced limitations.

Legal Controversies and Liability Cases

In Wyeth v. Levine (2009), the U.S. Supreme Court ruled 6-3 that federal Food and Drug Administration (FDA) approval of a drug's labeling does not preempt state-law failure-to-warn claims, allowing Diana Levine, a musician who suffered gangrene and partial arm amputation after an intravenous (IV) push administration of Phenergan (promethazine hydrochloride), to recover damages from manufacturer Wyeth. Levine received the injection during chemotherapy treatment for pregnancy-related nausea on April 4, 2000, resulting in inadvertent intra-arterial delivery that caused irreversible tissue necrosis despite existing label warnings about such risks. A Vermont jury awarded her approximately $7.4 million, including $2.4 million for medical expenses and $5 million for pain and suffering, finding the label deficient for not explicitly contraindicating IV push methods in favor of slower IV drip administration to mitigate the known 12 reported cases of gangrene and amputation linked to promethazine's formulation by that time. The decision rejected Wyeth's impossibility preemption argument—that complying with both FDA labeling standards and stricter state duties was infeasible—emphasizing that manufacturers retain a duty to update labels post-approval if new risks emerge, supported by evidence that promethazine's pH and insolubility heightened arterial injection hazards beyond general warnings. This ruling fueled ongoing debates on federal preemption in pharmaceutical liability, with critics arguing it exposes manufacturers to inconsistent state standards potentially conflicting with FDA expertise, while proponents cited empirical data on underreported adverse events (e.g., FDA's post-case review of 21 additional gangrene incidents) to affirm state courts' role in enforcing accountability for inadequate risk communication. Following the case, the FDA mandated a black box warning on promethazine labels in 2009, highlighting risks of severe tissue injury, including gangrene requiring amputation, specifically from IV administration. Subsequent product liability suits have invoked similar claims of manufacturer for neurotoxic effects and amputations tied to improper IV use, though settlements remain confidential in many instances; for example, Levine's underscored accountability for failing to prioritize safer delivery methods despite internal awareness of administration errors contributing to over 100 reports by 2000. These cases highlight causal links between promethazine's chemical properties—its low solubility and irritant potential—and harms when deviated from approved routes, without evidence of broad preemption shielding generic manufacturers from state duties.