Zynrelef

1 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



2 

1. NAME OF THE MEDICINAL PRODUCT 
 
Zynrelef (60 mg + 1.8 mg) / 2.3 mL prolonged-release wound solution  
 
Zynrelef (200 mg + 6 mg) / 7 mL prolonged-release wound solution  
 
Zynrelef (400 mg + 12 mg) / 14 mL prolonged-release wound solution 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each mL of solution contains 29.25 mg of bupivacaine and 0.88 mg of meloxicam. 
 
Zynrelef prolonged-release solution is provided in the following doses: 
• 60 mg/1.8 mg of bupivacaine/meloxicam. 
• 200 mg/6 mg of bupivacaine/meloxicam. 
• 400 mg/12 mg of bupivacaine/meloxicam. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Prolonged-release wound solution. 
 
Clear, pale yellow to yellow, viscous liquid. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Zynrelef is indicated for treatment of somatic postoperative pain from small- to medium-sized surgical 
wounds in adults (see section 5.1). 
 
4.2 Posology and method of administration 
 
Zynrelef should be administered in a setting where trained personnel and equipment are available to 
treat patients promptly who show evidence of neurological or cardiac toxicity. 
 
Posology 
 
The recommended dose depends upon the size of the surgical site and the volume required to coat the 
affected tissues within the surgical site that could result in pain generation. It should be ensured there 
is not an excess that could be expressed from the site during closure, especially for small confined 
surgical spaces (see section 4.4). 
 
The volume to be withdrawn accounts for the hold-up in the Luer lock applicator. Examples of the 
volume to be withdrawn and dose available for administration are as follows  : 
• Bunionectomy – up to 2.3 mL (60 mg/1.8 mg) 
• Open inguinal herniorrhaphy – up to 10.5 mL (300 mg/9 mg) 
 
The maximum total dose of Zynrelef to be applied must not exceed 400 mg/12 mg (about 14 mL). 
 
Use with other anaesthetics 



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When using Zynrelef with other local anaesthetics, overall local anaesthetic exposure must be 
considered through 72 hours. In total, the maximum administered dose of bupivacaine must not exceed 
400 mg/day. 
 
Special populations 
 
Elderly patients (≥ 65 years of age) 
Elderly patients should be given reduced doses commensurate with their age and physical condition. 
As elderly patients may have decreased renal function, this should be considered when performing 
dose selection. 
 
Renal impairment 
No dose adjustment of Zynrelef is necessary in patients with mild to moderate renal impairment (see 
section 5.2). The use of Zynrelef in patients with non-dialysed severe renal impairment is 
contraindicated (see section 4.3) and use in patients with dialysed severe renal impairment is not 
recommended (see section 4.4). 
 
Hepatic impairment 
No dose adjustment of Zynrelef is necessary in patients with mild to moderate hepatic impairment. 
Patients should be monitored for signs of worsening liver function (see sections 4.4 and 5.2). The use 
of Zynrelef in patients with severe hepatic impairment is contraindicated (see section 4.3). 
 
Paediatric population 
The safety and efficacy of Zynrelef in children and adolescents under 18 years of age have not been 
established. No data are available. 
 
Method of administration 
 
Intralesional use. 
 
Zynrelef is intended for application to the surgical site. 
 
Zynrelef is intended for single-dose administration. 
 
Zynrelef should only be prepared and administered with the sterile components provided in the 
procedure pack (vented vial spike, syringe, Luer lock applicator). Full instructions for use are provided 
in the package leaflet for use by healthcare professionals. 
 
Zynrelef should be applied into the surgical site following final irrigation and suction and prior to 
suturing. If multiple tissue layers are involved, the solution should be applied after final irrigation and 
suction of each layer before closing. 
 
Zynrelef is not injected, it should be applied without a needle to the tissue layers below the skin 
incision. The solution should not be applied to the skin. A sufficient amount of solution should be 
applied to coat the tissues. 
 
When using monofilament sutures, 3 or more knots are recommended, as contact with Zynrelef may 
cause a single knot to loosen or untie. 
 
For instructions on the preparation of the medicinal product before administration, see section 6.6. 
 
4.3 Contraindications 
 
• Hypersensitivity to the active substances or to any of the excipients listed in section 6.1. 
• Patients with a known hypersensitivity to any local amide-type anaesthetic or non-steroidal 

antiinflammatory drugs (NSAIDs). Meloxicam must not be given to patients who have 



4 

developed signs of asthma, nasal polyps, angioneurotic oedema, or urticaria following the 
administration of acetyl salicylic acid or other NSAIDs. 

• Third trimester of pregnancy (see section 4.6). 
• Coronary artery bypass graft (CABG) surgery (see section 4.4). 
• Severe heart failure (see section 4.4). 
• Severely impaired liver function (see section 4.4). 
• Non-dialysed severe renal failure (see section 4.4). 
 
4.4 Special warnings and precautions for use 
 
Efficacy and safety have not been established in major surgeries including abdominal, vascular and 
thoracic surgeries (see section 5.1). It is recommended not to use this medicine in major surgeries. 
 
Local anaesthetic systemic toxicity (LAST) 
 
As there is a potential risk of severe life-threatening adverse reactions associated with the 
administration of bupivacaine, any bupivacaine-containing product should be administered in a setting 
where trained personnel and equipment are available to promptly treat patients who show evidence of 
neurological or cardiac toxicity. 
 
Bupivacaine may cause acute toxicity effects on the central nervous and cardiovascular systems if 
utilised for local anaesthetic procedures resulting in high blood concentrations of the active substance. 
This is especially the case after unintentional intravascular administration or injection into highly 
vascular areas. Ventricular arrhythmia, ventricular fibrillation, sudden cardiovascular collapse, and 
death have been reported in connection with high systemic concentrations of bupivacaine. The 
clinician responsible should take the necessary precautions to avoid local anaesthetic systemic toxicity 
(see section 4.2). 
 
Patients who require special attention in order to reduce the risk of dangerous adverse reactions 
include the following: 
• The elderly and patients in poor general condition should be given reduced doses commensurate 

with their physical status. 
• Patients with partial or complete heart block – due to the fact that local anaesthetics may depress 

myocardial conduction. 
• Patients with advanced liver disease or severe renal dysfunction. 
 
The toxic effects of local anaesthetics are additive and their administration should be used with 
caution, including monitoring for neurologic and cardiovascular effects related to LAST. 
 
Cardiovascular system 
 
Clinical trial and epidemiological data suggest that use of some NSAIDs (particularly at high doses 
and in long term treatment) may be associated with a small increased risk of arterial thrombotic events 
(for example myocardial infarction or stroke). There are insufficient data to exclude such a risk for 
Zynrelef. The use of Zynrelef in patients with a recent myocardial infarction should be avoided unless 
the benefits are expected to outweigh the risk of recurrent cardiovascular thrombotic events. 
 
Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, 
peripheral arterial disease, and/or cerebrovascular disease should only be treated with Zynrelef after 
careful consideration. 
 
Gastrointestinal system 
 
Gastrointestinal (GI) bleeding, ulceration, or perforation, which can be fatal, have been reported with 
all NSAIDs at any time during treatment, with or without warning symptoms or a previous history of 
serious GI events. As Zynrelef contains meloxicam, an NSAID, health care professionals should 



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remain alert for signs and symptoms of GI ulceration and bleeding. If a serious GI adverse reaction is 
suspected, evaluation and treatment should be promptly initiated. 
 
The risk of GI bleeding, ulceration, or perforation is higher with increasing NSAID doses in patients 
with a history of ulcer and in the elderly. Combination therapy with protective medicinal products (e.g. 
misoprostol or proton pump inhibitors) should be considered for these patients and for patients 
requiring concomitant low-dose acetylsalicylic acid or other active substances likely to increase GI 
risk (see below and section 4.5). 
 
Patients with a history of GI toxicity, particularly when elderly, should be advised to report any 
unusual abdominal symptoms (especially GI bleeding). 
 
Caution is advised in patients receiving concomitant medicinal products which could increase the risk 
of ulceration or bleeding, such as heparin, anticoagulants such as warfarin, or other NSAIDs, including 
acetylsalicylic acid given at anti-inflammatory doses (≥ 1 g, as single intake, or ≥ 3 g, as total daily 
amount) (see section 4.5). 
 
Serious skin reactions 
 
Life-threatening cutaneous reactions (Stevens-Johnson syndrome [SJS] and toxic epidermal necrolysis 
[TEN]) have been reported with the use of meloxicam. Patients should be advised of the signs and 
symptoms and monitored closely for skin reactions. The highest risk for occurrence of SJS or TEN is 
within the first weeks of treatment. If the patient has developed SJS or TEN with the use of 
meloxicam, Zynrelef must not be administered in this patient at any time. 
 
Monitoring of liver and renal function 
 
Occasional increases in serum transaminase levels, increases in serum bilirubin or other liver function 
parameters, as well as increases in serum creatinine and blood urea nitrogen, as well as other 
laboratory disturbances, have been reported with meloxicam. The majority of these instances involved 
transitory and slight abnormalities. Patients should be monitored for signs of worsening liver or renal 
function. 
 
Renal toxicity and renal impairment 
 
Renal toxicity has been seen in patients in whom renal prostaglandins have a compensatory role in the 
maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-
dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may 
precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired 
renal function, nephrotic syndrome, lupus nephropathy, dehydration, hypovolemia, heart failure, 
severe liver dysfunction, those taking diuretics, angiotensin converting enzyme (ACE) inhibitors or 
angiotensin-II antagonists, and the elderly. 
 
Renal function should be monitored in patients with renal or hepatic impairment, heart failure, 
dehydration, or hypovolemia after administration of Zynrelef. 
 
The renal effects of meloxicam may hasten the progression of renal dysfunction in patients with 
pre-existing renal disease. 
 
No information is available from controlled clinical studies regarding the use of meloxicam in patients 
with advanced renal disease. Because some meloxicam metabolites are excreted by the kidney, the use 
of Zynrelef is not recommended in patients with dialysed severe renal impairment unless the benefits 
are expected to outweigh the risk of worsening renal function. Zynrelef is contraindicated in patients 
with non-dialysed severe renal impairment (see section 4.3). 
 
Hepatic impairment 
 



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Since bupivacaine is metabolized by the liver, high doses should be used cautiously in patients with 
hepatic disease. Patients with severe hepatic disease, because of their inability to metabolize local 
anaesthetics normally, are at a greater risk of developing toxic plasma concentrations. The use of 
Zynrelef in patients with severe hepatic impairment is contraindicated (see section 4.3). 
 
Hyperkalaemia 
 
Increases in serum potassium concentration, including hyperkalaemia, have been reported for 
meloxicam in patients with diabetes or receiving concomitant treatment known to increase potassium 
concentrations. Zynrelef should only be used in patients with hyperkalaemia if the benefits outweight 
the risks. 
 
Chondrolysis 
 
There have been post-marketing reports of chondrolysis in patients receiving postoperative 
intra-articular continuous infusion of local anaesthetics. The majority of reported cases of chondrolysis 
have involved the shoulder joint. Due to multiple contributing factors and inconsistency in the 
scientific literature regarding mechanism of action, causality has not been established. Intra-articular 
continuous infusion of Zynrelef should be avoided. 
 
Wound healing impairment 
 
Impaired wound healing has been observed in patients following bunionectomy (see section 4.8). For 
small, confined surgical spaces, avoid administration of excess volume (see section 4.2). 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Bupivacaine 
 
Bupivacaine should be used with caution in patients receiving other local anaesthetics or active 
substances structurally related to amide-type local anaesthetics, e.g. certain anti-arrhythmics, such as 
lidocaine and mexiletine, since the systemic toxic effects are additive (see section 4.4). 
 
Meloxicam 
 
ACE Inhibitors, Angiotensin-II Antagonists 
NSAIDs may decrease the antihypertensive effect of ACE inhibitors, angiotensin-II antagonists, or 
beta-blockers (including propranolol). 
 
In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal 
impairment, co-administration of an NSAID with ACE inhibitors or angiotensin-II antagonists may 
result in deterioration of renal function, including possible acute renal failure, which is usually 
reversible. 
 
Patients on ACE inhibitors, angiotensin-II antagonists, or beta-blockers should be monitored following 
treatment with Zynrelef to ensure that the desired blood pressure is obtained. Patients who are elderly, 
volume-depleted, or have impaired renal function, should be monitored for signs of worsening renal 
function (see section 4.4). 
 
Diuretics 
Patients on diuretics should be monitored following treatment with Zynrelef for signs of worsening 
renal function, in addition to assuring diuretic efficacy, including antihypertensive effects. 
 
Lithium 
NSAIDs have been reported to increase blood lithium levels (via decreased renal excretion of lithium), 
which may reach toxic values. The concomitant use of lithium and NSAIDs is not recommended. If 



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the use of Zynrelef with lithium appears necessary, patients should be monitored for signs of lithium 
toxicity following treatment with Zynrelef. 
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
 
There are no available human data on use of Zynrelef in pregnant women. 
 
Bupivacaine 
There is a limited amount of data from the use of bupivacaine in pregnant women. Animal studies 
have shown decreased pup survival and embryotoxic effects (see section 5.3). 
 
Meloxicam 
Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or the embryo-foetal 
development. Data from epidemiological studies suggest an increased risk of miscarriage and of 
cardiac malformation and gastroschisis after use of a prostaglandin synthesis inhibitor in early 
pregnancy. The absolute risk for cardiovascular malformation was increased from less than 1%, up to 
approximately 1.5%. The risk is believed to increase with dose and duration of therapy. In animals, 
administration of a prostaglandin synthesis inhibitor has been shown to result in increased pre- and 
post-implantation loss and embryo-foetal lethality. In addition, increased incidences of various 
malformations, including cardiovascular, have been reported in animals given a prostaglandin 
synthesis inhibitor during the organogenetic period. 
 
During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may expose the foetus to 
the following: 
• Cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary 

hypertension). 
• Renal dysfunction, which may progress to renal failure with oligohydroamnios. 
 
At the end of pregnancy, all prostaglandin synthesis inhibitors may expose the mother and the neonate 
to the following: 
• Possible prolongation of bleeding time, an anti-aggregating effect, which may occur even at 

very low doses. 
• Inhibition of uterine contractions resulting in delayed or prolonged labour. 
 
If Zynrelef is used by a woman attempting to conceive, or during the first and second trimester of 
pregnancy, the dose should be kept as low and duration of treatment as short as possible. 
 
Due to the meloxicam content, Zynrelef is contraindicated during the third trimester of pregnancy (see 
section 4.3). During the first and second trimester of pregnancy, meloxicam should not be given unless 
clearly necessary. 
 
Breast-feeding 
 
There are no available human data on the use of Zynrelef in breast-feeding women. 
 
Bupivacaine enters human milk and NSAIDs are also known to pass into human milk. A decision 
must be made whether to start or discontinue breast-feeding taking into account the benefit of breast-
feeding for the child and the benefit of Zynrelef for the woman. 
 
Fertility 
 
Studies evaluating the effects of Zynrelef on male and female fertility have not been performed. 
 



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The use of meloxicam may impair fertility in women attempting to conceive. In women who have 
difficulties conceiving or who are undergoing investigation of infertility, Zynrelef should only be used 
if the benefits outweigh the risks. 
 
4.7 Effects on ability to drive and use machines 
 
Bupivacaine has minor influence on the ability to drive and use machines. Zynrelef may have a very 
mild effect on mental function and coordination even in the absence of overt central nervous system 
(CNS) toxicity, and may temporarily impair locomotion and alertness. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
 
The most common adverse reaction was dizziness (15.1%). 
 
Tabulated list of adverse reactions 
 
The following adverse reactions are based on experience from clinical trials and displayed by system 
organ class and frequency in Table 1 below. Within each frequency grouping, adverse reactions are 
presented in order of decreasing seriousness. The frequency of the adverse reactions is expressed 
according to the following categories: very common (≥1/10); common (≥1/100 to <1/10). 
 
Table 1: Adverse reactions reported for Zynrelef 
 

System Organ Class Very Common Common 
Nervous system disorders Dizziness Dysgeusia 
Cardiac disorders  Bradycardia 

Vascular disorders  Hypotension 
Skin and subcutaneous tissue 
disorders 

 Skin odour abnormal 

General disorders and administration 
site conditions 

 
Cellulitis 
Impaired healing* 
Local site reaction 
Local site swelling 
Local site erythema 
Peripheral swelling 

* Impaired wound healing, including wound dehiscence, has been observed in patients following bunionectomy 
(a model of surgery with a small, confined space available to instill the product). 
 
Reporting of suspected adverse reactions 
 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
Bupivacaine 
 
Accidental intravascular injections of bupivacaine may cause immediate (within seconds to a few 
minutes) systemic toxic reactions. In the event of overdose, systemic toxicity appears later 
(15-60 minutes after injection) due to the slower increase in local anaesthetic blood concentration. 
 
Acute systemic toxicity 
Systemic toxic reactions primarily involve the CNS and the cardiovascular system. 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


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Central nervous system toxicity 
CNS toxicity is a graded response with symptoms and signs of escalating severity. The first symptoms 
are usually circumoral paraesthesia, numbness of the tongue, light-headedness, hyperacusis, tinnitus, 
and visual disturbances. Dysarthria, muscular twitching, or tremors are more serious and precede the 
onset of generalised convulsions. These signs must not be mistaken for neurotic behaviour. 
Unconsciousness and grand mal convulsions may follow, which may last from a few seconds to 
several minutes. Hypoxia and hypercarbia occur rapidly following convulsions due to the increased 
muscular activity, together with the interference with respiration and possible loss of functional 
airways. In severe cases apnoea may occur. Acidosis, hyperkalaemia, and hypoxia increase and extend 
the toxic effects of local anaesthetics. 
 
Recovery is due to redistribution of the local anaesthetic medicinal product from the central nervous 
system and subsequent metabolism and excretion. Recovery may be rapid unless large amounts of 
bupivacaine have been injected. 
 
Cardiovascular system toxicity 
Cardiovascular system toxicity may be seen in severe cases and is generally preceded by signs of 
toxicity in the central nervous system. In patients under heavy sedation or receiving a general 
anaesthetic, prodromal CNS symptoms may be absent. Hypotension, bradycardia, arrhythmia, and 
even cardiac arrest may occur as a result of high systemic concentrations of local anaesthetics, but in 
rare cases cardiac arrest has occurred without prodromal CNS effects. 
 
Treatment of acute toxicity 
If signs of acute systemic toxicity appear, administration of Zynrelef should be immediately stopped. 
 
At the first sign of toxicity, oxygen should be administered. 
 
The first step in the management of convulsions, as well as under ventilation or apnoea, consists of 
immediate attention to the maintenance of a patent airway and assisted or controlled ventilation with 
oxygen and a delivery system capable of permitting immediate positive airway pressure by mask. 
Immediately after the institution of these ventilatory measures, the adequacy of the circulation should 
be evaluated, keeping in mind that medicinal products used to treat convulsions sometimes depress the 
circulation when administered intravenously. Should convulsions persist despite adequate respiratory 
support, and if the status of the circulation permits, small increments of an ultra-short acting 
barbiturate (such as thiopental or thiamylal) or a benzodiazepine (such as diazepam) may be 
administered intravenously. The clinician should be familiar, prior to the use of anaesthetics, with 
these anticonvulsant medicinal products. Supportive treatment of circulatory depression may require 
administration of intravenous fluids and, when appropriate, a vasopressor dictated by the clinical 
situation (such as ephedrine to enhance myocardial contractile force). 
 
If not treated immediately, both convulsions and cardiovascular depression can result in hypoxia, 
acidosis, bradycardia, arrhythmias, and cardiac arrest. If cardiac arrest should occur, standard 
cardiopulmonary resuscitative measures should be instituted. 
 
Endotracheal intubation, employing medicinal products, and techniques familiar to the clinician, may 
be indicated after initial administration of oxygen by mask if difficulty is encountered in the 
maintenance of a patent airway or if prolonged ventilatory support (assisted or controlled) is indicated. 
 
Meloxicam 
 
There is limited experience with meloxicam overdose. 
 
Symptoms following acute NSAID overdose are usually limited to lethargy, drowsiness, nausea, 
vomiting, and epigastric pain, which are generally reversible with supportive care. Gastrointestinal 
bleeding can occur. Anaphylactoid reactions may occur following an overdose. 
 



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Patients should be managed with symptomatic and supportive care following an overdose of Zynrelef. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Anesthetics, Local anaesthesia drugs (amides), ATC code: not yet 
assigned 
 
Mechanism of action 
 
Zynrelef is a fixed-dose, prolonged-release combination of bupivacaine and meloxicam. For 
approximately 72 hours after Zynrelef is applied into the surgical site, it releases bupivacaine and 
meloxicam, which are then absorbed into the surrounding tissues. Meloxicam is believed to control the 
tissue inflammation thereby normalizing the pH and potentiating the effect of bupivacaine, resulting in 
an increase in analgesia. 
 
Bupivacaine is a local anaesthetic of the amide type with both anaesthetic and analgesic effects. At 
high doses it produces surgical anaesthesia, while at lower doses it produces sensory block (analgesia) 
with less pronounced motor block. 
 
Meloxicam is a non-steroidal anti-inflammatory drug (NSAID) of the oxicam family, with 
anti-inflammatory, analgesic, and antipyretic properties. Its precise mechanism of action remains 
unknown. Meloxicam inhibits the biosynthesis of prostaglandins, known inflammation mediators. 
 
Pharmacodynamic effects 
 
Bupivacaine 
Bupivacaine causes a reversible blockade of impulse propagation along nerve fibres by preventing the 
inward movement of sodium ions through the cell membrane of the nerve fibres. The sodium channels 
of the nerve membrane are considered a receptor for local anaesthetic molecules. 
 
Local anaesthetics may have similar effects on other excitable membranes, e.g. in the brain and 
myocardium. If excessive amounts of active substance reach the systemic circulation, symptoms and 
signs of toxicity may appear, emanating from the central nervous and cardiovascular systems. 
 
Central nervous system toxicity (see section 4.9) usually precedes the cardiovascular effects as central 
nervous system toxicity occurs at lower plasma concentrations. Direct effects of local anaesthetics on 
the heart include slow conduction, negative inotropism, and eventually cardiac arrest. 
 
Clinical efficacy and safety 
 
The efficacy of Zynrelef was evaluated in 2 multi-centre, double-blind, parallel-group, active- and 
placebo-controlled clinical trials. 
 
Study 301 (Bunionectomy) 
A total of 412 patients undergoing unilateral bunionectomy with osteotomy and fixation with a 
lidocaine Mayo block were randomized to 1 of the following 3 treatment groups in a 3:3:2 ratio 
(respectively): Zynrelef 60 mg/1.8 mg, bupivacaine hydrochloride 50 mg, or saline placebo. The mean 
patient age was 47 years (range 18 to 77 years) and patients were predominantly female (86%). 
Zynrelef was applied directly into the surgical site at the end of the procedure, after final irrigation and 
suction, but prior to closure. Bupivacaine hydrochloride and saline placebo were administered by 
injection and instillation, respectively. Pain intensity was rated by the patients on a 0 to 10 numeric 
rating scale (NRS) out to 72 hours post-dose. Postoperatively, there was no scheduled pain medication 
regimen; however, patients were allowed rescue medicinal products as needed (10 mg oxycodone 



11 

orally every 4 hours, 10 mg IV morphine every 2 hours, and/or 1,000 mg paracetamol orally every 
6 hours). 
 
Results for the primary endpoint and all 4 key secondary endpoints were positive. Zynrelef 
significantly reduced the mean AUC of the NRS-A pain intensity scores with activity through 
72 hours post-surgery compared with both saline placebo (primary endpoint) and bupivacaine HCl 
(Figure 1). Zynrelef also significantly reduced opioid consumption and significantly increased the 
proportion of subjects who required no postoperative opioid rescue medication (were “opioid-free”) 
(Table 2). 
 
Figure 1: Mean pain intensity over 72 hours in Study 301 (bunionectomy) 
 

 

 
Table 2: Opioid-use over 72 hours in Study 301 (bunionectomy) 
 

 
Zynrelef 

60 mg/1.8 mg 
(N = 157) 

Bupivacaine 
Hydrochloride 

50 mg 
(N = 155) 

Saline 
Placebo 

(N = 100) 

Total opioid 
consumptiona 
0-72 hours 

Median 13 18 25 
p-value vs saline placebo < 0.0001   
p-value vs bupivacaine 
hydrochloride 0.0022   

Opioid-free 
0-72 hours 

n (%) 45 (29%) 17 (11%) 2 (2%) 
p-value vs saline placebo < 0.0001   
p-value vs bupivacaine 
hydrochloride 0.0001   

a In intravenous morphine milligram equivalents (IV MME). 
 
Study 302 (Inguinal herniorrhaphy) 
A total of 418 patients undergoing open inguinal herniorrhaphy with mesh under general anaesthesia 
were randomized to 1 of the following 3 treatment groups in a 2:2:1 ratio (respectively): Zynrelef 
300 mg/9 mg, bupivacaine hydrochloride 75 mg, or saline placebo. The mean patient age was 49 years 
(range 18 to 83 years) and patients were predominantly male (94%). Zynrelef was applied directly into 

AUC0-72 
Zynrelef vs Placebo: p < 0.0001 

Zynrelef vs Bupivacaine HCl: p = 0.0002 

Zynrelef 60 mg/1.8 mg 
(N = 157) 

Bupivacaine HCl 
50 mg (N = 155) 

Saline Placebo 
(N = 100) 

N
R

S 
Pa

in
 In

te
ns

ity
 S

co
re

 (M
ea

n 
± 

SE
) 

 

Hours Post Study Administration 
 



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the surgical site at the end of the procedure, following irrigation and suction of each fascial layer but 
prior to closure. Bupivacaine hydrochloride and saline placebo were administered by injection and 
instillation, respectively. Pain intensity was rated by the patients on a 0 to 10 NRS out to 72 hours 
post-dose. Postoperatively, there was no scheduled pain medication regimen; however, patients were 
allowed rescue medicinal product as needed (10 mg oxycodone orally every 4 hours, 10 mg morphine 
IV every 2 hours, and/or 1,000 mg paracetamol orally every 6 hours). 
 
Results for the primary endpoint and all 4 key secondary endpoints were positive. Zynrelef 
significantly reduced the mean AUC of the NRS-A pain intensity scores with activity through 
72 hours post-surgery compared with both saline placebo (primary endpoint) and bupivacaine HCl 
(Figure 2). Zynrelef also significantly reduced opioid consumption and significantly increased the 
proportion of subjects who were “opioid-free” (Table 3). 
 
Figure 2: Mean pain intensity (NRS) over 72 hours in Study 302 (herniorrhaphy) 
 

 
 
 
 
Table 3: Opioid-use over 72 hours in in Study 302 (herniorrhaphy) 
 

 
Zynrelef 

300 mg/9 mg 
(N = 164) 

Bupivacaine 
Hydrochloride 

75 mg 
(N = 172) 

Saline 
Placebo 
(N = 82) 

Total opioid 
consumptiona 
0-72 hours 

Median 0 7 11 
p-value vs saline placebo 0.0001   
p-value vs bupivacaine 
hydrochloride 0.0240   

Opioid-free 
0-72 hours 

n (%) 84 (51%) 69 (40%) 18 (22%) 
p-value vs saline placebo < 0.0001   
p-value vs bupivacaine 
hydrochloride 0.0486   

a In intravenous morphine milligram equivalents (IV MME). 
 
Surgeries not evaluated with Zynrelef 
Efficacy and safety have not been established in major surgeries including abdominal, vascular and 
thoracic surgeries (see section 4.4). 

AUC0-72 
Zynrelef vs Placebo: p = 0.0004 

Zynrelef vs Bupivacaine HCl: p < 0.0001 

Zynrelef 300 mg/9 mg 
(N = 164) 

Bupivacaine HCl 75 mg 
(N = 172) 

Saline Placebo 
(N = 82) 

Hours Post Study Administration 

N
R

S 
Pa

in
 In

te
ns

ity
 S

co
re

 (M
ea

n 
± 

SE
) 

 



13 

 
Paediatric population 
 
The European Medicines Agency has deferred the obligation to submit the results of studies with 
Zynrelef in one or more subsets of the paediatric population in the treatment of acute post-operative 
pain (see section 4.2 for information on paediatric use). 
 
5.2 Pharmacokinetic properties 
 
Local application of Zynrelef into the surgical site results in detectable systemic plasma levels of 
bupivacaine through 72 hours and meloxicam through 120 hours. Systemic plasma levels of 
bupivacaine following application of Zynrelef are correlated with efficacy. 
 
Absorption 
 
Zynrelef is a prolonged-release formulation of bupivacaine and meloxicam using a polymer-based 
drug delivery system. Following single-dose application of Zynrelef, bupivacaine and meloxicam are 
released simultaneously from the polymer for approximately 3 days. 
 
Pharmacokinetic parameters of bupivacaine and meloxicam from Zynrelef were evaluated following 
multiple surgical procedures. 
 
Descriptive statistics of pharmacokinetic parameters of representative Zynrelef doses in each study are 
provided in Table 4. 
 
Table 4: Summary of pharmacokinetic parameters for bupivacaine and meloxicam after 
administration of single doses of Zynrelef 
 

Active 
Ingredient Parameter 

Bunionectomy: 
Zynrelef 

60 mg/1.8 mg 
(N = 17) 

Herniorrhaphy: 
Zynrelef 

300 mg/9 mg 
(N = 16) 

Bupivacaine 

Cmax (ng/mL) 53.6 (32.6) 271 (147) 
tmax (h) 3.00 (1.55-24.08) 18.22 (3.10-30.28) 
AUC(0-t) (h×ng/mL) 1,650 (1,130) 14,900 (8,470) 
AUC(inf) (h×ng/mL) 1,680 (1,190) 15,300 (8,780) 

Meloxicam 

Cmax (ng/mL) 25.6 (13.8) 225 (96.3) 
tmax (h) 18.02 (8.13-60) 53.72 (24.2-96.02) 
AUC(0-t) (h×ng/mL) 1,600 (915) 18,600 (7,860) 
AUC(inf) (h×ng/mL) 1,660 (1,050) 15,500 (NCa) 

AUC = area under the curve; NC = not calculated. 
Note: Arithmetic mean (standard deviation) except tmax where it is median (range). Doses of Zynrelef are shown 
as bupivacaine dose (mg)/meloxicam dose (mg).  
a Terminal elimination phase was not captured in a sufficient number of patients; SD was not calculated. 
 
Distribution 
 
After bupivacaine and meloxicam have been released from Zynrelef and are absorbed systemically, 
bupivacaine and meloxicam distribution is expected to be the same as for any bupivacaine 
hydrochloride solution or meloxicam oral formulation. 
 
Bupivacaine 
Bupivacaine has a total plasma clearance of 0.58 L/min, a volume of distribution at steady state of 
73 L and an intermediate hepatic extraction ratio of 0.38 after IV administration. It is mainly bound to 
alpha-l-acid glycoprotein with plasma binding of 96%. 



14 

 
Meloxicam 
Meloxicam is very strongly bound to plasma proteins, essentially albumin (99%). Meloxicam 
penetrates into synovial fluid to give concentrations approximately half of those in plasma. Volume of 
distribution is low, on average 11 L. Inter-individual variation is in the order of 30-40%. 
 
Biotransformation 
 
Bupivacaine 
Bupivacaine is extensively metabolised in the liver, predominantly by aromatic hydroxylation to 
4-hydroxy-bupivacaine and N-dealkylation to pipecoloxylidide (PPX), both mediated by cytochrome 
P450 (CYP) 3A4. The plasma concentrations of PPX and 4-hydroxy-bupivacaine after administration 
of bupivacaine are low as compared to the parent medicinal product. The metabolites have a 
pharmacological activity that is less than that of bupivacaine. 
 
Meloxicam 
Meloxicam undergoes extensive hepatic biotransformation. Four different metabolites of meloxicam 
were identified in urine, which are all pharmacodynamically inactive. The major metabolite, 
5'-carboxymeloxicam (60% of dose), is formed by oxidation of an intermediate metabolite 
5'-hydroxymethylmeloxicam, which is also excreted to a lesser extent (9% of dose). In vitro studies 
suggest that CYP2C9 plays an important role in this metabolic pathway, with a minor contribution 
from the CYP3A4 isoenzyme. The patient's peroxidase activity is probably responsible for the other 
two metabolites, which account for 16% and 4% of the administered dose respectively. 
 
Elimination 
 
After bupivacaine and meloxicam have been released from Zynrelef and are absorbed systemically, 
their excretion is expected to be the same as for other bupivacaine hydrochloride solution formulations 
or meloxicam oral formulations. 
 
Bupivacaine 
About 1% of bupivacaine is excreted in the urine as unchanged drug in 24 hours and approximately 
5% as PPX. The mean apparent terminal half-life (t1/2) for bupivacaine from Zynrelef is approximately 
14 to 15 hours. 
 
Meloxicam 
Meloxicam is excreted predominantly in the form of metabolites and occurs to equal extents in urine 
and faeces. Less than 5% of the daily dose is excreted unchanged in faeces, while only traces of the 
parent compound are excreted in urine. The mean apparent terminal half-life (t1/2) for meloxicam from 
Zynrelef is approximately 22 to 25 hours. Total plasma clearance amounts on average 8 mL/min. 
 
Special populations 
 
After bupivacaine and meloxicam have been released from Zynrelef and are absorbed systemically, 
the effects of hepatic and renal impairment are expected to be the same as for other bupivacaine and 
meloxicam formulations. 
 
Hepatic/renal impairment 
Clearance of bupivacaine is almost entirely due to liver metabolism and is more sensitive to changes in 
intrinsic hepatic enzyme function than to liver perfusion. 
 
Neither hepatic, nor mild nor moderate renal impairment, has a substantial effect on meloxicam 
pharmacokinetics. In severe renal failure, the increase in the volume of distribution may result in 
higher free meloxicam concentrations (see sections 4.3 and 4.4). 
 
Elderly 



15 

Following oral dosing of meloxicam, mean plasma clearance at steady state in elderly subjects was 
slightly lower than that reported for younger subjects. 
 
5.3 Preclinical safety data 
 
Non-clinical data on Zynrelef, bupivacaine, or meloxicam reveal no special hazard for humans based 
on conventional studies of general toxicity and toxicity to reproduction and development. 
 
No evidence has been found of any mutagenic effect of meloxicam, either in vitro or in vivo. No 
carcinogenic risk for meloxicam has been found in the rat and mouse at doses far higher than those 
used clinically. Long-term studies in animals to evaluate the mutagenic and carcinogenic potential of 
Zynrelef and bupivacaine have not been conducted. 
 
Bupivacaine crosses the placenta. In reproduction toxicity studies, decreased survival of the offspring 
of rats and embryolethality was noted in rabbits at bupivacaine doses, which were 1.9- or 2.1-fold the 
maximum recommended daily dose of Zynrelef in humans (based on body surface area using 
maximum daily exposure in a 60 kg person). A study in rhesus monkeys of bupivacaine suggested 
altered postnatal behaviour following exposure to bupivacaine at birth. 
 
Oral reproductive studies of meloxicam in the rat have shown a decrease of ovulations and inhibition 
of implantations and embryotoxic effects (increase of resorptions) at maternotoxic dose levels at 
1 mg/kg and higher. Studies of toxicity on reproduction in rats and rabbits did not reveal teratogenicity 
up to oral doses of 4 mg/kg in rats and 80 mg/kg in rabbits. These no observed effect levels exceeded 
the maximum daily exposure of meloxicam in Zynrelef by a factor of 7.4- and 295-fold (based on 
body surface area using maximum daily exposure in a 60 kg person). Foetotoxic effects at the end of 
gestation, shared by all prostaglandin synthesis inhibitors, have been described. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
DETOSU/triethylene glycol/triethylene glycol polyglycolide copolymer 
Triacetin 
Dimethyl sulfoxide 
Maleic acid 
 
6.2 Incompatibilities 
 
This medicinal product must not be mixed with water, sodium chloride solution, or other medicinal 
products as the product will become very viscous and difficult to administer. 
 
Zynrelef should not come in contact with povidone-iodine solution. 
 
6.3 Shelf life 
 
2 years 
Shelf-life after first opening: use immediately. 
 
6.4 Special precautions for storage 
 
Do not store above 25°C. 
Store in the original package in order to protect from light and moisture. 
This medicinal product should only be prepared immediately prior to use. 
 
6.5 Nature and contents of container  
 



16 

60 mg bupivacaine/1.8 mg meloxicam 
 
One 10 mL Type I glass vial, 1 vented vial spike, one 3 mL Luer lock syringe, and 1 Luer lock 
applicator. 
 
200 mg bupivacaine/6 mg meloxicam 
 
One 10 mL Type I glass vial, 1 vented vial spike, one 12 mL Luer lock syringe, and 1 Luer lock 
applicator. 
 
400 mg bupivacaine/12 mg meloxicam 
 
One 20 mL Type I glass vial, 1 vented vial spike, two 12 mL Luer lock syringes, and 2 Luer lock 
applicators. 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal and other handling 
 
Only clear solution without particles should be used. 
 
The solution is for single-use. Any unused solution should be discarded. 
 
The exterior of the Zynrelef vial is not sterile. Aseptic technique must be strictly observed throughout 
handling of the medicinal product to keep it free from microbial contamination. For operating room 
preparation it is recommended that a 2-person team prepares this product. 
 
Zynrelef is a viscous solution that should only be prepared and administered with the components 
provided in the Zynrelef procedure pack. 
 
Refer to the instructions for use intended for healthcare professionals presented in the package leaflet. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Heron Therapeutics, B.V. 
Herengracht 500 
1017 CB Amsterdam 
Netherlands 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/20/1478/001 
EU/1/20/1478/002 
EU/1/20/1478/003 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu.  

http://www.ema.europa.eu/


17 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

 
A. MANUFACTURER(S) RESPONSIBLE FOR BATCH 

RELEASE 
 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 
AND USE 

 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE 

MARKETING AUTHORISATION 
 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 
THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT 

 
 



18 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer(s) responsible for batch release 
 
Millmount Healthcare Limited 
Block-7, City North Business Campus 
Stamullen K32 YD60 
Co. Meath 
Ireland 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
• Periodic safety update reports (PSURs) 
 
The requirements for submission of PSURs for this medicinal product are set out in the list of 
Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC 
and any subsequent updates published on the European medicines web-portal. 
 
The marketing authorisation holder (MAH) shall submit the first PSUR for this product within 
6 months following authorisation. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
• Risk management plan (RMP) 

 
The marketing authorisation holder (MAH) shall perform the required pharmacovigilance 
activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the 
marketing authorisation and any agreed subsequent updates of the RMP. 
 
An updated RMP should be submitted: 

• At the request of the European Medicines Agency; 
• Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached. 

 
 
  



19 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
  



20 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
  



21 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Zynrelef (60 mg + 1.8 mg) / 2.3 mL prolonged-release wound solution  
bupivacaine/meloxicam 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each mL of solution contains 29.25 mg of bupivacaine and 0.88 mg of meloxicam. 
 
Each vial delivers a dose of 60 mg/1.8 mg of bupivacaine/meloxicam. 
 
 
3. LIST OF EXCIPIENTS 
 
Also contains: DETOSU/triethylene glycol/triethylene glycol polyglycolide copolymer, triacetin, 
dimethyl sulfoxide, maleic acid. 
 
See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Prolonged-release wound solution  
 
1 x 10 mL vial, 1 vented vial spike, 1 Luer lock syringe, and 1 Luer lock applicator. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Intralesional use. 
For single use only. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 



22 

9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 25°C. 
Store in the original package in order to protect from light and moisture. 
Prepare immediately prior to use. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Heron Therapeutics, B.V. 
Herengracht 500 
1017 CB Amsterdam 
Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/20/1478/001 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted. 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN 
  



23 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
VIAL CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Zynrelef (60 mg + 1.8 mg) / 2.3 mL prolonged-release wound solution  
bupivacaine/meloxicam 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each mL of solution contains 29.25 mg of bupivacaine and 0.88 mg of meloxicam. 
 
Each vial delivers a dose of 60 mg/1.8 mg of bupivacaine/meloxicam. 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Prolonged-release wound solution 
1 x 10 mL vial 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Intralesional use. 
For single use only. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 25°C. 
Store in the original package in order to protect from light. 
Prepare immediately prior to use. 
 



24 

 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Heron Therapeutics, B.V. 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/20/1478/001 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted. 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
 
  



25 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Zynrelef (60 mg + 1.8 mg) / 2.3 mL prolonged-release wound solution  
bupivacaine/meloxicam 
Intralesional use 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
60 mg/1.8 mg/dose 
 
 
6. OTHER 
 
 
  



26 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Zynrelef (200 mg + 6 mg) / 7 mL prolonged-release wound solution 
bupivacaine/meloxicam 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each mL of solution contains 29.25 mg of bupivacaine and 0.88 mg of meloxicam. 
 
Each vial delivers a dose of 200 mg/6 mg of bupivacaine/meloxicam. 
 
 
3. LIST OF EXCIPIENTS 
 
Also contains: DETOSU/triethylene glycol/triethylene glycol polyglycolide copolymer, triacetin, 
dimethyl sulfoxide, maleic acid. 
 
See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Prolonged-release wound solution 
 
1 x 10 mL vial, 1 vented vial spike, 1 Luer lock syringe, and 1 Luer lock applicator. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Intralesional use. 
For single use only. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 



27 

9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 25°C. 
Store in the original package in order to protect from light and moisture. 
Prepare immediately prior to use. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Heron Therapeutics, B.V. 
Herengracht 500 
1017 CB Amsterdam 
Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/20/1478/002 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted. 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN  



28 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
VIAL CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Zynrelef (200 mg + 6 mg) / 7 mL prolonged-release wound solution  
bupivacaine/meloxicam 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each mL of solution contains 29.25 mg of bupivacaine and 0.88 mg of meloxicam. 
 
Each vial delivers a dose of 200 mg/6 mg of bupivacaine/meloxicam. 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Prolonged-release wound solution 
1 x 10 mL vial 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Intralesional use. 
For single use only. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 25°C. 
Store in the original package in order to protect from light. 
Prepare immediately prior to use. 
 



29 

 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Heron Therapeutics, B.V. 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/20/1478/002 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted. 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
 
  



30 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Zynrelef (200 mg + 6 mg) / 7 mL prolonged-release wound solution 
bupivacaine/meloxicam 
Intralesional use 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
200 mg/6 mg/dose 
 
 
6. OTHER 
 
 
  



31 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Zynrelef (400 mg + 12 mg) / 14 mL prolonged-release wound solution 
bupivacaine/meloxicam 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each mL of solution contains 29.25 mg of bupivacaine and 0.88 mg of meloxicam. 
 
Each vial delivers a dose of 400 mg/12 mg of bupivacaine/meloxicam. 
 
 
3. LIST OF EXCIPIENTS 
 
Also contains: DETOSU/triethylene glycol/triethylene glycol polyglycolide copolymer, triacetin, 
dimethyl sulfoxide, maleic acid. 
 
See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Prolonged-release wound solution 
 
1 x 20 mL vial, 1 vented vial spike, 2 Luer lock syringes, and 2 Luer lock applicators. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Intralesional use. 
For single use only. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 



32 

9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 25°C. 
Store in the original package in order to protect from light and moisture. 
Prepare immediately prior to use. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Heron Therapeutics, B.V. 
Herengracht 500 
1017 CB Amsterdam 
Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/20/1478/003 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted. 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN  



33 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
VIAL CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Zynrelef (400 mg + 12 mg) / 14 mL prolonged-release wound solution  
bupivacaine/meloxicam 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each mL of solution contains 29.25 mg of bupivacaine and 0.88 mg of meloxicam. 
 
Each vial delivers a dose of 400 mg/12 mg of bupivacaine/meloxicam. 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Prolonged-release wound solution 
1 x 20 mL vial 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Intralesional use. 
For single use only. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 25°C. 
Store in the original package in order to protect from light. 
Prepare immediately prior to use. 
 



34 

 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Heron Therapeutics, B.V. 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/20/1478/003 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted. 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
 
  



35 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Zynrelef (400 mg + 12 mg) / 14 mL prolonged-release wound solution 
bupivacaine/meloxicam 
Intralesional use 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
400 mg/12 mg/dose 
 
 
6. OTHER 
 
 
 
  



36 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



37 

Package leaflet: Information for the patient 
 

Zynrelef (60 mg + 1.8 mg) / 2.3 mL prolonged-release wound solution  
 

Zynrelef (200 mg + 6 mg) / 7 mL prolonged-release wound solution  
 

Zynrelef (400 mg + 12 mg) / 14 mL prolonged-release wound solution 
 

bupivacaine/meloxicam 
 
Read all of this leaflet carefully before you are given this medicine because it contains important 
information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor, pharmacist or nurse. 
- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
 
1. What Zynrelef is and what it is used for 
2. What you need to know before you are given Zynrelef 
3. How you will be given Zynrelef 
4. Possible side effects 
5. How to store Zynrelef 
6. Contents of the pack and other information 
 
 
1. What Zynrelef is and what it is used for 
 
Zynrelef contains the medicines bupivacaine and meloxicam. 
• Bupivacaine belongs to a group of medicines called local anaesthetics. 
• Meloxicam belongs to a group of medicines called non-steroidal anti-inflammatory drugs 

(NSAIDs). 
 
Zynrelef will be applied during surgery by your doctor. 
 
Zynrelef is used in adults to reduce pain from small- to medium-sized surgical wounds after surgery. 
 
 
2. What you need to know before you are given Zynrelef 
 
You must not be given Zynrelef: 
• if you are in your last trimester of pregnancy (30 weeks onwards). See section on pregnancy; 
• if you are allergic to bupivacaine and/or meloxicam or any of the other ingredients of this 

medicine (listed in section 6); 
• if you are allergic to other local anaesthetics of the same class as bupivicaine (such as 

lidocaine, mepivacaine, prilocaine, levobupivacaine, and ropivacaine); 
• if you have ever developed any of the following after taking acetyl salicylic acid, a 

substance present in many medicines used to relieve pain and lower fever, as well as to 
prevent blood clotting, or other non-steroidal anti-inflammatories : 
- wheezing, chest tightness, breathlessness (asthma) 
- nasal blockage due to swellings in the lining of your nose (nasal polyps) 
- skin rashes/nettle rash (urticaria) or serious skin reactions 
- sudden skin or mucosal swelling, such as swelling around the eyes, face, lips, mouth or 

throat, possibly making breathing difficult (angioneurotic oedema) 
• during a heart bypass surgery (coronary artery bypass graft); 
• if you have severe heart failure; 



38 

• if you have severe liver problems; 
• if you have severe kidney failure and not receiving dialysis. 
 
If you are not sure if any of the above applies to you, talk to your doctor before you are given 
Zynrelef. 
 
Warnings and precautions 
 
Talk to your doctor, pharmacist or nurse before receiving Zynrelef: 
• if you have heart problems, previous stroke or think that you might be at risk of these conditions 

because medicines such as meloxicam present in Zynrelef may be associated with a small 
increased risk of heart attack (“myocardial infarction”) or stroke. 

• if you have ever had bleeding from your stomach or gastro-intestinal tract, a stomach ulcer, or 
inflammation of the stomach (gastritis) because medicines such as meloxicam present in 
Zynrelef may worsen these conditions. 

• if you develop signs of skin reactions, especially within the first weeks after surgery. Your 
doctor will closely monitor skin reactions, and Zynrelef must never be administered to you 
again. 

• if you have impaired kidney function or kidney disease. 
• if you have impaired liver function or liver disease. 
• if you have high potassium levels in your blood (hyperkalaemia). 
• if you are having a surgery to fix a bunion in your foot because impaired wound healing has 

been observed in patients following this surgery. Your doctor should be aware to avoid the 
administration of an excess volume of Zynrelef. 

 
Chondrolysis (breakdown of the cartilage) has been reported in patients receiving postoperative 
intra-articular continuous infusion of local anaesthetics (one of the ingredients of this medicine). Your 
doctor should be aware that Zynrelef is not intended to be used for administration via an intra-articular 
route. 
 
If you are not sure if any of the above applies to you, talk to your doctor or pharmacist before you are 
given Zynrelef. 
 
Children and adolescents 
 
Zynrelef is not recommended for use in children and adolescents below 18 years of age. 
 
Other medicines and Zynrelef 
 
Tell your doctor if you are taking, have recently taken or might take any other medicines. This is 
because Zynrelef can affect the way some medicines work. 
 
In particular, tell your doctor or pharmacist if you are taking/have taken or are using any of the 
following: 
• medicines used to treat an uneven heart beat (arrhythmia), such as lidocaine and mexiletine. 
 
Your doctor needs to know about these medicines to be able to work out the correct dose of Zynrelef 
for you. 
 
Also, tell your doctor if you are taking any of the following medicines: 
• medicines to treat heart and kidney diseases (such as ACE inhibitors, angiotensin receptor 

blockers, or beta-blockers); 
• any diuretic medicine (“water tablets”). Your doctor may monitor your kidney function if you 

are taking diuretics; 
• lithium - used to treat mood disorders. 
 



39 

If you are in doubt about any of these medicines, ask your doctor. 
 
Pregnancy, breast-feeding and fertility 
 
Tell your doctor immediately if you are pregnant or breast-feeding, think you may be pregnant or are 
planning to have a baby. Meloxicam, one of the medicines in Zynrelef, may make it more difficult to 
become pregnant. If you have difficulties conceiving or you are undergoing investigation for fertility, 
your doctor will decide if Zynrelef should be given to you. 
Zynrelef must not be administered during the last three months of pregnancy because Zynrelef 
can have serious side effects on your unborn child, in particular heart, lung and kidney effects, 
even with only one administration. During the first 6 months of pregnancy, your doctor will decide 
if Zynrelef should be given to you. Zynrelef is not recommended during breast-feeding. 
 
Driving and using machines 
 
Zynrelef may have a very mild effect on your mental function and coordination, and may temporarily 
impair your locomotion and alertness. After you have been given Zynrelef, you should not drive or use 
tools or machines until after these effects wear off. 
 
 
3. How you will be given Zynrelef 
 
Zynrelef will be applied during surgery by your doctor. 
Your doctor will determine the correct dose for you depending on the type of surgery you are having. 
Your doctor may decide to reduce the dose if you are elderly. 
 
Your doctor will ensure you have the correct amount of pain relief at all times. 
 
If you have been given too much Zynrelef 
 
Serious side effects from getting too much Zynrelef need special treatment and the doctor treating you 
is trained to deal with these situations. 
 
Seek medical help as soon as possible if you experience any of these early signs of being given too 
much Zynrelef: 
• feeling dizzy or light-headed; 
• numbness of the lips and around the mouth; 
• numbness of the tongue; 
• hearing problems; 
• problems with your vision. 
 
More serious side effects from being given too much Zynrelef include problems with your speech, 
twitching of your muscles, tremors, trembling, fits (seizures), and loss of consciousness. If any of 
these occur, seek medical help immediately. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Important side effects to look out for: 
 
Side effects reported in clinical studies for patients treated with Zynrelef were: 
 
Very common (may affect more than 1 in 10 people): 
• dizziness 



40 

 
Common (may affect up to 1 in 10 people): 
• abnormally slow heart beat; 
• low blood pressure; 
• unpleasant body smell; 
• infection of the skin (cellulitis); 
• abnormal healing, including reopening of the wound, at the site of bunion surgery; 
• swelling, redness, heat or infection at the site of surgery; 
• swelling of your lower legs or hands; 
• altered taste. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor. This includes any possible side effects not listed in this 
leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. 
By reporting side effects you can help provide more information on the safety of this medicine. 
 
 
5. How to store Zynrelef 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the carton after “EXP”. The expiry 
date refers to the last day of that month. 
 
Do not store above 25°C. 
Store in the original package in order to protect from light and moisture. 
 
Your doctor or the hospital will normally store Zynrelef and they are responsible for the quality of the 
medicine when it has been opened if it is not used immediately. The medicine should be visually 
inspected prior to use. The solution should only be used if it is clear, practically free from particles and 
if the container is undamaged. Your doctor will throw away the medicine appropriately. 
 
 
6. Contents of the pack and other information 
 
What Zynrelef contains 
- The active substances are bupivacaine and meloxicam. Each mL of solution contains 29.25 mg 

bupivacaine and 0.88 mg meloxicam. 
-  Zynrelef prolonged-release solution is provided in the following doses: 

• 60 mg/1.8 mg of bupivacaine/meloxicam. 
• 200 mg/6 mg of bupivacaine/meloxicam. 
• 400 mg/12 mg of bupivacaine/meloxicam. 

- The other ingredients are DETOSU/triethylene glycol/triethylene glycol polyglycolide 
copolymer, triacetin, dimethyl sulfoxide and maleic acid. 

 
What Zynrelef looks like and contents of the pack 
 
Zynrelef is a prolonged-release wound solution for intralesional use (application to surgical site). It is 
a clear, pale yellow to yellow solution. 
 
Each Zynrelef pack contains 1 x 10 mL or 1 x 20 mL single-use glass vial, contained in an individual 
carton and sterile individually packaged components for preparation and administration: 
• 60 mg bupivacaine and 1.8 mg meloxicam: one 10 mL single-dose vial, 1 vented vial spike, one 

3 mL Luer lock syringe, and 1 Luer lock applicator. 
• 200 mg bupivacaine and 6 mg meloxicam: one 10 mL single-dose vial, 1 vented vial spike, one 

12 mL Luer lock syringe, and 1 Luer lock applicator. 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


41 

• 400 mg bupivacaine and 12 mg meloxicam: one 20 mL single-dose vial, 1 vented vial spike, 
two 12 mL Luer lock syringes, and 2 Luer lock applicators. 

 
Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder 
Heron Therapeutics, B.V. 
Herengracht 500 
1017 CB Amsterdam 
Netherlands 
 
Manufacturer 
Millmount Healthcare Limited 
Block-7, City North Business Campus 
Stamullen K32 YD60 
Co. Meath 
Ireland 
 
This leaflet was last revised in 
 
Detailed information on this medicine is available on the European Medicines Agency website: 
http://www.ema.europa.eu. 
 
------------------------------------------------------------------------------------------------------------------------ 
 
The following information is intended for healthcare professionals only: 
 
INSTRUCTIONS FOR USE FOR ZYNRELEF 
 
1. Zynrelef is intended for single-dose administration only. 
2. Zynrelef is supplied as a procedure pack consisting of a single-dose glass vial, and the following 

sterile components: Luer lock syringe(s), a vented vial spike, and Luer lock applicator(s). 
3. Zynrelef is a viscous solution that should only be prepared and administered with the 

components provided in the Zynrelef procedure pack. 
4. The contents of the Zynrelef vial are sterile. The vial exterior is not sterile. Aseptic technique 

must be strictly observed throughout handling of the medicinal product to keep it free from 
microbial contamination. 

 
Preparation 
The following 3 procedure packs are available for Zynrelef: 
 

Product Presentation Syringe size 
Number of 

syringes 

Volume to 
withdraw per 

syringea 

Volume 
administered 

60 mg/1.8 mg of 
bupivacaine/meloxicam solution in a 
10 mL vial 

3 mL 1 2.3 mL 2.0 mL 

200 mg/6 mg of 
bupivacaine/meloxicam solution in a 
10 mL vial 

12 mL 1 7 mL 6.7 mL 

400 mg/12 mg of 
bupivacaine/meloxicam solution in a 
20 mL vial 

12 mL 2 7 mL (14 mL total) 
13.5 mL 

a Volume withdrawn includes Luer lock applicator hold-up volume. 



42 

Instructions for preparation and administration 
 
For operating room preparation, it is recommended that a 2-person team prepares this product: 
one sterile (shown in blue) and one non-sterile (shown in green). 
 

1. Prepare 
components 

2. Prepare vial 3. Remove protective 
sheath 

4. Attach vented vial 
spike 

    
STERILE NON-STERILE STERILE STERILE 
Open all components 
onto sterile field. 
Note: Prepare all 
syringe(s) provided in 
kit. 
Do not substitute any of 
the components. 
 

A) Flip cap off of vial 
and place onto 
stable non-sterile 
surface. 

B) Cleanse septum with 
alcohol wipe. 

C) Hold the vial in 
place for the sterile 
person to safely 
insert the vented 
vial spike. 

Do not remove the 
stopper or attempt to 
pour the vial contents. 

A) Remove blue 
protective sheath 
from vented vial 
spike. 

B) Remove Luer cap. 
 

Push the spike through 
the septum of the vial 
until it “snaps” into 
place. 
Hold the vented vial 
spike by the adapter 
neck to maintain sterility 
of the vented vial spike 
and sterile person. 
 
NON-STERILE 
Hold the vial in place 
while sterile person 
attaches spike. 
Note: It is recommended 
to do this on a firm, flat 
surface. 

 
 
  



43 

5. Prepare syringe 6. Prepare for 
withdrawal 

7. Withdraw product 8. Attach Luer lock 
applicator 

 
 

   

STERILE STERILE STERILE STERILE 

Fill the syringe with the 
same amount of air as 
the amount of product 
you plan to withdraw. 
Air from syringe will be 
pushed into the vial at 
Step 7 after the vial has 
been inverted and 
product has filled the 
neck of the vial. 
 

Attach the air-filled 
syringe to the vented vial 
spike. 
Note: Avoid pushing or 
pumping the plunger rod 
up and down at any point 
in the withdrawal 
process. 
 
NON-STERILE 
Hold the vial in place 
until the syringe is 
attached. 

A) Invert the vial using 
the syringe. 

B) Allow product to fill 
the neck of the vial. 

C) Push air into vial 
and wait for the air 
bubble to rise. 

D) Withdraw the 
product into the 
syringe. It is normal 
for there to be small 
air bubbles in the 
syringe. 

Note: Product is very 
thick. It may take a few 
minutes to withdraw. 
 
NON-STERILE 
You may assist the 
sterile person with 
inverting the vial if 
necessary by holding the 
non-sterile vial. 

A) Return vial to non-
sterile surface. 

B) Remove syringe 
from vial and attach 
Luer lock 
applicator. 

C) Place syringe on 
sterile surface. 

D) (if needed) Repeat 
steps 5-8 with 
second syringe. 

 
NON-STERILE 
Hold the vial in place for 
attachment of second 
syringe, if needed. 

 
This medicinal product should only be prepared immediately prior to use. This medicinal product 
cannot be prepared and stored in advance of use. 
 
Administration Instructions – This information should be reviewed before using the medicinal 
product for the first time. Zynrelef should only be administered with the syringe and Luer lock 
applicator provided in the procedure pack. 
 
1. Zynrelef is applied without a needle into the surgical site following final irrigation and suction 

and prior to suturing. Only apply Zynrelef after final irrigation and suction of each layer before 
closing, if multiple tissue layers are involved. 

2. Using the Luer lock applicator attached to the syringe, apply Zynrelef to the tissues within the 
surgical site that could result in pain generation. 

3. Use a sufficient amount to coat the tissues. For small spaces, ensure there is not an excess that 
could be expressed from the site during closure. 

 
4. Only apply Zynrelef to the tissue layers below the skin incision and not directly onto the skin. 



44 

5. The amount of Zynrelef required depends upon the surgical area of tissue to be treated. The 
maximum total dose volume is approximately 14 mL. Zynrelef spreads easily and covers a large 
area. 

6. Zynrelef does not degrade sutures. When using monofilament sutures, 3 or more knots are 
recommended as contact with Zynrelef may cause a single knot to loosen or untie. 

 
Disposal 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET