WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS Cardiovascular Thrombotic Events ·         Non-steroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use. ·         Ibuprofen is contraindicated in the setting of coronary artery bypass graft (CABG) surgery Gastrointestinal Bleeding, Ulceration and Perforation ·         NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events

QUALITATIVE AND QUANTITATIVE COMPOSITION

Boschofen 400mg/100mL Infusion
Each 100mL vial contains:
Ibuprofen BP…. 400mg
(Product Specs.: Innovator’s)

PHARMACEUTICAL FORM
Infusion

CLINICAL PARTICULARS

Therapeutic indications
Boschofen is indicated in adults and pediatric patients aged 3 months and older for the:

• Management of mild to moderate pain
• Management of moderate to severe pain as an adjunct to opioid analgesics
• Reduction of fever

Posology and method of administration
Use should be limited to situations where oral administration is inappropriate. Patients must switch to oral treatment as soon as this is possible.

This medicinal product is indicated for the shortest period needed. Treatment should not exceed 3 days. Adequate hydration of the patient should be maintained to minimize the risk of possible adverse reactions at renal level.

Adults
For Analgesia (pain): The dose is 400mg to 800mg intravenously every 6 hours as necessary. Infusion time must be at least 30 minutes. Maximum daily dose is 3,200mg.

For Fever: The dose is 400mg intravenously, followed by 400mg every 4 to 6 hours or 100mg to 200mg every 4 hours as necessary. Infusion time must be at least 30 minutes. Maximum daily dose is 3,200mg.

Pediatric Patients
For Analgesia (pain) and Fever: (Ages 12 to 17 years)

The dose is 400mg intravenously every 4 to 6 hours as necessary. Infusion time must be at least 10 minutes. Maximum daily dose is 40mg/kg or 2,400mg, whichever is less.

Ages 6 months to less than 12 years
The dose is 10mg/kg intravenously up to a maximum single dose of 400mg every 4 to 6 hours as necessary. Infusion time must be at least 10 minutes. Maximum daily dose is 40mg/kg or 2,400mg, whichever is less.

Age Group	Dose	Dosing Interval	Min infusion time	Max daily dose
6 months to less than 12 years	10mg/kg up to 400mg max	Every 4 to 6 hours as Necessary	10 minutes	*40mg/Kg or 2,400mg
12 to 17 years	400mg	Every 4 to 6 hours as Necessary	10 minutes	*40mg/kg or 2,400mg

Ages 3 months to less than 6 months: The dose is a single dose at 10mg/kg intravenously up to a maximum single dose of 100mg. Infusion time must be at least 10 minutes.

Renal insufficiency
Precautions should be taken when NSAIDs are used in patients with renal insufficiency. In patients with mild or moderate renal impairment, the initial dose should be reduced and be kept as low as possible for the shortest duration necessary to control symptoms and renal function monitored. This medicinal product is contraindicated in patients with severe renal insufficiency.

Hepatic insufficiency
Precautions should be taken when NSAIDs are used in this population. Patients with mild or moderate hepatic insufficiency should start the treatment with reduced doses, the dose should be kept as low as possible for the shortest duration necessary and they should be carefully monitored. This medicinal product is contraindicated in patients with severe hepatic insufficiency.

Method of administration:
For intravenous use. This medicinal product should only be administered by qualified healthcare professionals in an environment where appropriate equipment is available (during treatment).

The solution should be administered as an intravenous infusion over 30 minutes.

Contraindications

• Hypersensitivity to the active substance, to other NSAIDs
• A history of bronchospasm, asthma, rhinitis, angioedema or urticaria associated with taking acetylsalicylic acid (ASA) or other non-steroidal anti-inflammatory drugs (NSAIDs).
• Conditions involving an increased tendency or active bleeding such as thrombocytopenia
• Active, or history of recurrent peptic ulcer/haemorrhage/ GI bleeding or perforation
• Cerebrovascular or other active bleeding
• Severe hepatic or renal insufficiency
• Severe heart failure
• Severe dehydration (caused by vomiting, diarrhoea or insufficient fluid intake)
• Pregnancy, in the last trimester

Special warnings and precautions for use
Undesirable effects may be minimized by using the lowest effective dose for the shortest possible time necessary to control symptoms. Concomitant use of Ibuprofen with NSAIDs, including cyclooxygenase-2 selective inhibitors (Coxib), should be avoided.

Gastrointestinal risks:
GI bleeding, ulceration or perforation, which can be fatal, have been reported during treatment with all NSAIDs with or without warning symptoms or a previous history of serious GI events. These patients should commence treatment on the lowest dose available.

Combination therapy with protective agents (e.g., misoprostol or proton pump inhibitors) should be considered for these patients, and also for patients requiring concomitant low dose acetylsalicylic acid (ASA), or other drugs likely to increase the gastrointestinal risk. Patients with a history of GI toxicity, particularly in the elderly, should report any unusual GI bleeding particularly in the initial stages of treatment. Caution should be advised in patients receiving concomitant medications, which could increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin, selective serotonin-reuptake inhibitors or anti-platelet agents such as acetylsalicylic acid (ASA). NSAIDs should be given with care to patients with a history of gastrointestinal disease (ulcerative colitis, Crohn’s disease) as these conditions may be exacerbated.

Cardiovascular and cerebrovascular effects: Patients with uncontrolled hypertension, congestive heart failure (NYHA II-III), established ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with ibuprofen after careful consideration and high doses (2400mg/day) should be avoided.

Post myocardial infarction (MI) patients: Avoid the use of Ibuprofen in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent cardiovascular thrombotic events.

Severe skin reactions: Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis have been reported rarely in association with the use of NSAIDs. Ibuprofen should be discontinued.

Hepatic or renal insufficiency: Ibuprofen should be used with caution in patients with a history of liver or kidney disease . It should be administered in these patients at the lowest dose possible, and patient´s renal function should be regularly monitored. In case of dehydration, ensure sufficient fluid intake. Use special caution in dehydrated patients, Regular use of analgesics, especially when combining of different analgesic substances, can lead to kidney damage with the risk of renal insufficiency (analgesic nephropathy). This risk is higher in the elderly and patients with renal insufficiency, heart failure, liver dysfunction, those taking diuretics or ACE inhibitors.

As with other NSAIDs, ibuprofen can cause mild transient increases in some liver function parameters as well as significant increases in transaminases. If there is a significant increase in these parameters, treatment should be discontinued.

Anaphylactoid Reactions: Close patient monitoring is recommended, especially at the beginning of the infusion to detect any anaphylactic reaction caused by the active substance or the excipients. Severe acute hypersensitivity reactions (e.g., anaphylactic shock) are very rarely observed. At the first signs of a hypersensitivity reaction following the administration of Ibuprofen, therapy must be stopped and symptomatic treatment must be established.

Respiratory disorders: Caution is required if this medicinal product is administered to patients suffering from, or with a previous history of, bronchial asthma, chronic rhinitis or allergic diseases since NSAIDs have been reported to cause bronchospasm, urticaria or angioedema in such patients.

Hematological Effects: Ibuprofen may temporarily inhibit the blood-platelet function (thrombocyte aggregation), increasing the bleeding time and the risk of haemorrhage. Ibuprofen should only be used with particular caution in patients receiving Acetylsalicylic acid (ASA) to inhibit platelet aggregation. Patients with coagulation disorders or those undergoing surgery should therefore be monitored.

Through concomitant consumption of alcohol, active substance-related undesirable effects, particularly those that concern the gastrointestinal tract or the central nervous system, may be increased on use of NSAIDs.

Aseptic Meningitis: Some cases of aseptic meningitis have been reported with the use of ibuprofen in patients with systemic lupus erythematosus (SLE). therefore, should be taken into account when administering this treatment

Ophthalmological Effects: Blurred or diminished vision, scotomata, and changes in colour vision have been reported with oral ibuprofen. Discontinue ibuprofen if the patient develops such complaints.

Others: Prolonged use of painkillers may cause headache that must not be treated with increased doses of the medicinal product. Exceptionally, varicella can cause serious cutaneous and soft tissues infectious complications. Thus, it is advisable to avoid use of Ibuprofen in case of varicella.

Renal tubular acidosis and hypokalaemia may occur following acute overdose and in patients receiving ibuprofen products over long periods at high doses (typically greater than 4 weeks), including doses exceeding the recommended daily dose.

Masking of symptoms of underlying infections: Ibuprofen can mask symptoms of infection, which may lead to delayed initiation of appropriate treatment and thereby worsening the outcome of the infection. When Ibuprofen is administered for fever or pain relief in relation to infection, monitoring of infection is advised.

Interference with analytical tests: Bleeding time (may be extended for a day after discontinuation of therapy), blood glucose concentration (may decrease), creatinine clearance (may decrease), haematocrit or haemoglobin (may decrease), blood levels of urea nitrogen and serum creatinine and potassium (may increase), increased transaminase values with liver function tests.

Interaction with other medicinal products and other forms of interaction
Other NSAIDs, including COX-2 inhibitors and salicylates: As a result of synergist effects, the concurrent administration of two or more NSAIDs may increase the risk of gastrointestinal ulcers and bleeding. Co-administration of ibuprofen with other NSAIDs should therefore be avoided.
Concomitant administration of ibuprofen and acetylsalicylic acid is not generally  recommended because of the potential of increased adverse effects.

Lithium: Co-administration of ibuprofen with lithium-containing medicinal products can increase the serum level of lithium. Checking the serum lithium level is necessary.

Cardiac glycosides (Digoxin): NSAIDs may exacerbate cardiac failure, reduce glomerular filtration rate and increase plasma levels of cardiac glycosides. Monitoring of serum digoxin is recommended.

Phenytoin: Plasmatic levels of phenytoin may be increased in the concomitant treatment with ibuprofen and therefore the risk of toxicity may increase.

Antihypertensive (Diuretics, ACE inhibitors, beta-receptor blocking medicines and angiotensin-II antagonists: Diuretics and ACE-inhibitors may increase the nephrotoxicity of NSAIDs. NSAIDs can reduce the effect of diuretics and other antihypertensive drugs, including ACE-inhibitors and beta-blockers. In patients with reduced kidney function (e.g., dehydrated patients or elderly patients with reduced kidney function) the concomitant use of an ACE inhibitor and angiotensin-II antagonists with a cyclo-oxygenase-inhibiting medicinal product can lead to further impairment of kidney function, and to acute renal failure. The concomitant administration of ibuprofen and ACE-inhibitors may lead to hyperkalaemia.

Potassium sparing diuretics: Concomitant use may cause hyperkalaemia (check of serum potassium is recommended).

Captopril: Ibuprofen counteracts the effect of captopril of increased sodium excretion.

Corticosteroids: Increased risk of gastrointestinal ulceration or bleeding

Anti-platelet agents (e.g., clopidogrel and ticlopidine) and selective serotonin reuptake inhibitors (SSRIs): Increased risk of gastrointestinal bleeding. NSAIDs should not be combined with ticlopidine due to the risk of an additive effect in the inhibition of platelet function.

Methotrexate: NSAIDs inhibit the tubular secretion of methotrexate and certain metabolic interactions may occur resulting in decreased clearance of methotrexate. Therefore, concomitant use of NSAIDs and high doses of methotrexate should be avoided. In combined treatment, renal function should be monitored.

Ciclosporin: The risk of a kidney-damage by ciclosporin is increased by the concomitant administration of certain non-steroidal anti-inflammatory drugs. This effect cannot be ruled out for a combination of ciclosporin and ibuprofen either.

Anti-coagulants: NSAIDs may enhance the effect of anti-coagulants, such as warfarin. In case of simultaneous treatment, monitoring of the coagulation state is recommended.

Sulphonylureas: NSAIDs can increase the hypoglycaemic effect of sulphonylureas. In the case of simultaneous treatment, monitoring of blood glucose levels is recommended.

Tacrolimus: Elevated risk of nephrotoxicity.

Zidovudine: There may be an increased risk of haematoxicity during concomitant use of zidovudine and NSAIDs.

Probenecid and sulfinpyrazone: May delay the excretion of ibuprofen.

Quinolone antibiotics: Patients having NSAIDs and quinolones may have an increased risk of developing convulsions.

CYP2C9 Inhibitors: Concomitant administration may increase the exposure to ibuprofen (CYP2C9 substrate).

Mifepristone: If NSAIDs are used within 8-12 days after the mifepristone administration, they may decrease the effect of mifepristone.

Alcohol: Increased risk of significant GI adverse effects, including bleeding.

Aminoglycosides: May decrease the excretion of aminoglycosides and increase their toxicity.

Herbal extracts: Ginkgo biloba may potentiate the risk of bleeding with NSAIDs.

Fertility, Pregnancy and lactation
Pregnancy: During the first and second trimester of pregnancy, ibuprofen should not be given unless clearly necessary. Ibuprofen use is contraindicated during the third trimester of pregnancy.

Breast-feeding: Ibuprofen and its metabolites can pass in low concentrations into the breast milk. No harmful effects to infants are known to date, so for short-term treatment with lower doses interruption of breast-feeding would generally not be necessary.

Fertility: There is some evidence that drugs which inhibit cyclo-oxygenase/ prostaglandin synthesis may cause impairment of female fertility by an effect on ovulation.

Effects on ability to drive and use machines
Ibuprofen, in single or short-term use, has no or negligible influence on the ability to drive and use machines. The occurrence of relevant undesirable effects such as fatigue and vertigo can impair reactivity, and the ability to drive a vehicle and/or use machines may be reduced.

Undesirable effects
The following frequencies are taken as a basis when evaluating undesirable effects:

Very common: ≥ 1/10, Common: ≥ 1/100 to< 1/10, Uncommon: ≥ 1/1,000 to< 1/100, Rare: ≥ 1/10,000 to< 1/1,000, Very rare: <1/10,000, Not known: frequency cannot be estimated from the available data.

System Organ Class	Undesirable Effects	Frequency
Infections and infestations	Super infections due to resistant bacteria or fungi e.g. oral and vaginal candidiasis	Common
Blood and lymphatic system disorders	Anemia Leucopenia(s) Neutropenia, Thrombocytopenia, Thrombocythemia, Blood eosinophilia, Prothrombin time, prolonged/ INR increased	Uncommon
	Prothrombin level increased/ INR decreased Agranulocytosis Pancytopenia	Very rare
Immune system disorders	Allergic reaction	Uncommon
	Anaphylaxis incl. very rarely life-threatening shock Allergic oedema/ angioedema (incl. laryngeal oedema, potentially life-threatening)	Rare
Endocrine disorders	Syndrome of inappropriate Antidiuretic Hormone Secretion (SIADH)	Very rare
Metabolism and Nutrition disorders	Hyperlipidemia	Uncommon
	Hyperglycemia, Hyperuricemia	Rare
	Hypoglycemia, Hypoglycemic coma	Very rare
Psychiatric disorders	Anxiety , Psychomotor , hyperactivity/agitation	Uncommon
	Emotional lability, Depression (in very rare cases potentially culminating in self-injurious behavior, such as suicidal ideations/ thoughts, or suicide attempts, Hallucination and Delirium	Rare
	Depersonalization, Psychotic Reactions (potentially culminating in self-injurious behavior, such as suicidal ideations/thoughts, or suicide attempts)	Very rare
Nervous system disorders	Headache and dizziness	Common
	Par- and Dysaesthesia, Taste disorders (incl. ageusia in very rare cases), Confusion and disorientation, sleep disorders (predominantly insomnia), Tremor, Vertigo and Somnolence.	Uncommon
	Hypoesthesia, Smell disorders (incl. anosmia), Abnormal dreams, Disturbed coordination (incl. gait disturbances, esp. due to dizziness or vertigo), Seizures incl. grand mal convulsions, Disturbed attention. Speech disorders, Amnesia, Peripheral, neuropathy and polyneuropathy	Rare
	Hyperesthesia	Very rare
Eye disorders	Visual disturbances incl. diplopia and blurred vision (especially in the course of CNS reactions)	Uncommon
	Photophobia	Rare
	Transient loss of vision (especially in the course of CNS reactions), Uveitis and bilateral acute iris transillumination	Very rare
Ear and labyrinth disorders	Tinnitus, Hearing impairment incl. deafness (usually reversible)	Rare
Cardiac disorders	QT prolongation in patients with hypokalemia	Common
	QT prolongation, Palpitations, Tachycardia, Atrial fibrillation and  Angina pectoris	Uncommon
	Ventricular tachyarrhythmias, Syncope (i.e., acute and short lasting loss of consciousness)	Rare
	Unspecified Arrhythmias, Torsade de Pointes and Cardiac arrest	Very rare
Vascular disorders	Vasodilatation	Uncommon
	Hypertension and Hypotension	Rare
	Vasculitis	Very rare
Respiratory, thoracic and mediastinal disorders	Dyspnea (including Asthmatic conditions)	Uncommon
Gastrointestinal Disorders	Nausea, Vomiting, Gastrointestinal, Diarrhea and abdominal pains	Common
	Decreased appetite and food intake Constipation, Dyspepsia, Flatulence, Gastritis and Increased amylase	Uncommon
	Dysphagia, Stomatitis, Antibiotic-associated colitis (incl. pseudomembranous colitis, in very rare cases associated with life-threatening Complications)	Rare
Hepatobiliary Disorders	Increase in transaminases	Common
	Hepatic, impairment (incl. LDH increase), Increased bilirubin, Increased gamma-glutamyl transferase Increase in blood Alkaline phosphatase	Uncommon
	Jaundice and Hepatitis (predominantly cholestatic)	Rare
	Fulminant hepatitis potentially leading to lifethreatening liver failure (incl. fatal cases)	Very rare
Skin and subcutaneous tissue disorders	Pruritus, Rash, Urticaria and Dry skin	Uncommon
	Bullous skin reactions like Stevens-Johnson syndrome or toxic epidermal Necrolysis (potentially life-threatening)	Very rare
	Acute Generalized Exanthematous Pustulosis (AGEP)	Not known

System Organ Class	Undesirable Effects	Frequency
Musculoskeletal and connective tissue disorders	Arthralgia and Myalgia	Uncommon
	Tendonitis, Muscle cramp, Muscle twitching and Muscle weakness	Rare
	Tendon rupture, Arthritis, Muscle rigidity and Exacerbation of symptoms of myasthenia gravis	Very rare
	Rhabdomyolysis	Not known
Renal and urinary disorders	Dehydration	Uncommon
	Renal impairment (incl. increase in BUN and creatinine) and Renal failure	Rare
General disorders and administration site condition	Injection and infusion site reactions	Common
	Feeling unwell (predominantly asthenia or fatigue) Painful conditions (incl. pain in back, chest, pelvic and extremities) Sweating and Infusion site (thrombo- phlebitis)	Uncommon
	Edema	Rare

Overdose
Treatment is symptomatic and there is no specific antidote. The therapeutic possibilities for treatment of intoxication are dictated by the extent, level and clinical symptoms according to the common intensive care practices.

PHARMACOLOGICAL PROPERTIES
Pharmacodynamic properties
Therapeutic Classification: Anti-inflammatory and antirheumatic products, non-steroids.
Propionic acid derivatives
ATC code: M01AE01

Mechanism of Action
Ibuprofen has analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action of Ibuprofen, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2).

Pharmacokinetic properties
Absorption: Ibuprofen is administered intravenously, therefore there is no absorption process and bioavailability of ibuprofen is 100%. After intravenous administration of ibuprofen in humans, the maximum concentration (Cmax) of S- enantiomer (active) and R-enantiomer is reached at approximately 40 minutes, with a rate of infusion of 30 minutes.

Distribution: The estimated volume of distribution is 0.11 to 0.21L/kg. Ibuprofen is extensively bound to plasma proteins, primarily albumin.

Biotransformation: Ibuprofen is metabolised in the liver into two inactive metabolites, and these together with unmetabolized ibuprofen, are excreted by the kidney either as such or as conjugates. After an oral application, ibuprofen is already partly absorbed in the stomach and then completely in the small intestine. Following hepatic metabolisation (hydroxylation, carboxylation), the pharmacologically inactive metabolites are completely eliminated, mainly renally (90 %), but also with the bile.

Elimination: Excretion by the kidney is rapid and complete. The elimination half-life is about 2 hours.

Linearity / non-linearity: Ibuprofen shows linearity in the area under the curve of plasma concentration-time after a single administration of ibuprofen (in a range of 200 – 800mg).

For patients with mild renal impairment: Increased unbound (S)-ibuprofen, higher AUC values for (S)-ibuprofen and increased enantiomeric AUC (S/R) ratios have been reported compared with healthy controls.

In end-stage renal disease patients receiving dialysis the mean free fraction of ibuprofen was about 3% compared with about 1% in healthy volunteers. Severe impairment of renal function may result in accumulation of ibuprofen metabolites. The significance of this effect is unknown. The metabolites can be removed by haemodialysis.

Hepatic impairment:
In cirrhotic patients with moderate hepatic impairment (Child Pugh’s score 6-10) treated with racemic ibuprofen an average 2-fold prolongation of the half-life was observed and the enantiomeric AUC ratio (S/R) was significantly lower compared to healthy controls, suggesting an impairment of metabolic inversion of (R)-ibuprofen to the active (S)-enantiomer

PHARMACEUTICAL PROPERTIES
Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

Shelf life: 02 years

Special precautions for storage

• Protect from heat & sunlight, store below 25°C. The expiration date refers to the product correctly stored at the required condition.
• Do not refrigerate or freeze.
• Infusion should not be used if container is leaking, solution is cloudy or it contains undissolved particles.
  Keep out of the reach of children.
• For single use in one patient only.

To be sold on the prescription of a registered medical practitioner only.

Nature and contents of container and presentation
1’s (100mL vial)

REGISTRATION HOLDER / MARKETING AUTHORIZATION HOLDER
Head office:
Bosch Pharmaceuticals (Pvt.) Ltd.,
8, Modern Society, Tipu Sultan Road, Karachi-Pakistan

Manufacturer:
Bosch Pharmaceuticals (Pvt.) Ltd.,
209, Sector 23, Korangi Industrial area, Karachi-Pakistan

REGISTRATION / MARKETING AUTHORIZATION NUMBER
105334

DATE FROM WHICH MARKETING IS AUTHORIZED/ RENEWAL OF THE AUTHORIZATION
25-11-2020

DATE OF REVISION OF THE TEXT
29-05-2024