Medications & Clinical Interactions
FDA “black boxed-warning” drugs
(selected, high-frequency examples – not an exhaustive list)
1. Central nervous system & psychotropics
- All SSRIs/SNRIs & most other antidepressants
- – ↑ risk of suicidal thinking/behaviour in people ≤ 24 y
- close monitoring mandated
- Benzodiazepine class (e.g. diazepam, alprazolam, clonazepam)
- class-wide box (2020) for abuse, dependence, withdrawal, life-threatening respiratory depression (especially with opioids/alcohol)
- Opioids ± benzodiazepines
- combined use has boxed warning for profound sedation and fatal respiratory depression
- Clozapine
- Agranulocytosis (REMS/WBC monitoring)
- seizures
- myocarditis
- ↑ mortality in dementia psychosis
- Atypical antipsychotics (e.g. risperidone, olanzapine, quetiapine)
- ↑ cerebrovascular event
- all-cause mortality in elderly with dementia psychosis (class warning).
- Valproate (sodium/acid)
- fatal hepatotoxicity (highest in < 2 y)
- teratogenicity
- pancreatitis
2. Respiratory / allergy
- Montelukast
- serious neuro-psychiatric events incl. suicidality
- reserve for asthma where benefit > risk
- avoid first-line rhinitis use
3. Anti-infectives
- Systemic fluoroquinolones (ciprofloxacin, norfloxacin, moxifloxacin, etc.))
- disabling & potentially irreversible tendinopathy/rupture
- peripheral neuropathy
- CNS effects
- MG exacerbation
4. Cardiometabolic / endocrine
- GLP-1 receptor agonists
- (semaglutide – Ozempic®, Wegovy®, Rybelsus®; liraglutide)
- risk of medullary thyroid carcinoma
- contraindicated in MEN-2 or personal/family MTC
- Metformin
- (& fixed-dose combos)
- Lactic acidosis (rare but 50 % fatal)
- Contra-indicate eGFR <30 mL/min
- pause in sepsis, hypoxia, iodinated contrast
- All DOACs (apixaban, rivaroxaban, dabigatran, edoxaban)
- (A) thrombotic events if stopped early
- (B) spinal/epidural haematoma risk with neuraxial procedures
- Statins – no boxed warning (frequent misconception).
5. Immunology / rheumatology
- Methotrexate (all formulations)
- embryo-fetal toxicity
- fatal myelosuppression
- hepatotoxicity
- use only when benefits outweigh risks & with strict monitoring
- JAK inhibitors (tofacitinib, upadacitinib, baricitinib)
- – ↑ MACE, malignancy
- thrombosis
- serious infection & death
- use after TNF-i failure
- TNF-α inhibitors
- serious infection & malignancy in paediatrics/adolescents (class).
6. Dermatology / teratogens
- Isotretinoin
- severe birth-defects risk
- dispensing only under pregnancy-prevention program
- Thalidomide-analogues (thalidomide, lenalidomide, pomalidomide)
- embryo-fetal death
- specialist prescribing under REVLIMID/IMiD REMS (also adopted by TGA).
7. Antiepileptics / mood stabilisers
- Valproate
- Teratogenic (major malformations & neurodevelopmental delay)
- Absolute last-line in people who can become pregnant
- written pregnancy-prevention plan mandatory
- Carbamazepine
- Severe dermatological reactions (SJS/TEN)
- Consider pharmacogenetic test in pts of Asian ancestry
- stop drug at first rash
- Lamotrigine
- Life-threatening rash (SJS/TEN)
- Slow 6-week titration
- halt therapy at any mucocutaneous symptom
7. Other notable boxed-warning agents in common Australian use
| Drug/class | Key boxed warning | notes |
|---|---|---|
| Amiodarone | Pulmonary fibrosis hepatotoxicity pro-arrhythmia | Second-line anti-arrhythmic baseline LFT/PFT. |
| Teriparatide | Osteosarcoma in rat models | PBS-listed for severe osteoporosis avoid if bone malignancy risk. |
| Testosterone† | (2025 update) blood-pressure rise prior CV warning remains under review | Schedule 4 check CV risk & monitor BP |
| Opioid class | Addiction, abuse fatal overdose neonatal withdrawal | All S8 opioids TGA aligns with FDA boxed wording. |
| Bupropion & varenicline | Serious neuro-psychiatric events (re-worded 2016) | PBS smoking-cessation counsel on mood change. |
† not technically a “boxed” warning in Australia yet, but FDA wording triggers TGA review; class label updated Feb 2025
MEDICATIONS AND KEY INTERACTIONS
| Drug / Example(s) | Pharmacological class | Key clinical concerns (interactions ↔ adverse effects) | Practical GP notes |
|---|---|---|---|
| Thiazide & thiazide-like diuretics • hydrochlorothiazide • indapamide | Diuretic | • ↓ urate excretion → precipitates gout • Electrolyte shifts: ↓K⁺, ↓Na⁺, ↑Ca²⁺, ↑glucose, ↑lipids | • Avoid in active gout; baseline & 1-month EUC, then yearly • Triple-whammy (ACEi/ARB + NSAID + thiazide) ⇒ AKI |
| Loop diuretics • frusemide | Diuretic | • Ototoxicity (esp. with aminoglycosides) • ↓K⁺/Mg²⁺ • Volume depletion | • Slow IV push if >40 mg • Add K⁺/Mg²⁺ supplementation where needed 1-month EUC, then yearly • Triple-whammy (ACEi/ARB + NSAID + loop diuretic) ⇒ AKI |
| Potassium-sparing diuretics • spironolactone | Aldosterone antagonist | Hyperkalaemia hyponatraemia gynaecomastia | • Stop K⁺ supplements/ACEi + ARB combo • Check K⁺/eGFR at 1 & 4 weeks, then q3–6 months |
| ACE inhibitors • perindopril | RAAS inhibitor | Cough, hyperkalaemia 30–40 % creatinine bump angio-oedema (↑ risk ATSI) | • Baseline & 1–2 wk EUC • Hold in diarrhoea, sepsis or contrast (“sick-day” list) |
| ARBs • irbesartan | RAAS inhibitor | • Similar renal/K⁺ issues as ACEi • no cough | • Preferred if ACEi cough/angio-oedema |
| Calcium-channel blockers – dihydropyridines • amlodipine | Vasoselective CCB | • Peripheral oedema • gingival hyperplasia • reflux flare | • Oedema due to precapillary dilation – diuretics unhelpful |
| Calcium-channel blockers – non-DHP • diltiazem, verapamil | Rate-limiting CCB | • Bradycardia • heart block • constipation (verapamil) • CYP3A4 inhibitor | • Avoid with β-blocker in HFrEF unless specialist advice |
| β-blockers • metoprolol, bisoprolol | β-adrenergic antagonist | • Bronchospasm in asthma • masks hypoglycaemia • fatigue • vivid dreams | • Cardioselective agents (bisoprolol) safest in mild asthma/COPD |
| Statins • atorvastatin | HMG-CoA reductase inhibitor | • Myalgia/myositis • ↑LFTs • new-onset DM, CYP3A4 interactions (macrolides, azoles) | • Withhold during short-course clarithro/erythro; consider rosuvastatin |
| Ezetimibe | Cholesterol-absorption inhibitor | • Well tolerated • occasional myalgia ↑ when combined with statin | • PBS PBS unrestricted benefit when LDL target unmet on statin |
| PCSK9-mAbs • evolocumab | Monoclonal antibody | • Injection site reaction | • s/c 2- or 4-weekly; PBS under lipid clinic criteria |
| Combined oral contraceptive pill (COCP) | Oestrogen + progestogen | • VTE • ↑BP • ↓ efficacy with enzyme inducers (rifampicin, carbamazepine, St John’s wort) | • Category B3–D drug dep. on formulation; avoid in migraine + aura |
| Menopausal hormone therapy (MHT/HRT) | Oestrogen ± progestogen | • VTE, stroke (oral route) • breast Ca (≥5 y) | • Transdermal patches lower VTE risk; review annually |
| SGLT2 inhibitors • dapagliflozin | Oral antihyperglycaemic | • Genital mycosis • euglycaemic DKA • volume depletion | • Stop 2–3 days pre-surgery/illness; PBS for T2DM, HF, CKD |
| GLP-1 RAs • semaglutide | Injectable incretin mimetic | • Nausea • delayed gastric emptying • pancreatitis | • Weight-loss benefit; PBS for BMI ≥ OHS only via bariatric clinic (current) |
| Sulfonylureas • gliclazide MR | Insulin secretagogue | • Hypoglycaemia • weight gain | • Safer than glibenclamide; caution if irregular meals/renal |
| Metformin | Biguanide | • GI upset, lactic acidosis if eGFR < 30 or hypoxia | • Hold for contrast or severe illness; restart when eGFR stable |
| Insulin (all types) | Hormone | • Hypoglycaemia • lipohypertrophy | • Rotate sites; adjust for driving, fasting, exercise |
| Aminoglycosides • gentamicin | Antibiotic | • Ototoxicity • nephrotoxicity • neuromuscular blockade | • Use ideal body weight dosing; random level if course >48 h |
| Macrolides • clarithromycin, erythromycin | Antibiotic / CYP3A4 inhibitor | • QT prolongation • ↑ Statin/ colchicine/ DOAC levels | • Azithro safer re CYP but still QT |
| Fluoroquinolones • ciprofloxacin | Antibiotic | • Tendon rupture • dysglycaemia • QT prolongation • C. difficile | • Avoid <18 y, pregnancy; counsel re tendon pain |
| Tetracyclines • doxycycline | Antibiotic | • Photosensitivity • oesophagitis • chelates Ca²⁺ | • Take with water, upright; avoid <8 y & pregnancy |
| Nitrofurantoin | Antibiotic | • Pulmonary fibrosis (long-term) • peripheral neuropathy | • Contra eGFR < 45; only for uncomplicated cystitis |
| Trimethoprim (+/- sulfamethoxazole) | Antifolate | • Hyperkalaemia • bone-marrow suppression • ↑INR with warfarin | • Check K⁺/creat 3–5 d after start if on ACEi/ARB/K-sparing |
| Vancomycin IV | Glycopeptide | • Nephrotoxicity • “red man” histamine reaction | • Trough target 15-20 mg/L for deep infection; infuse ≥1 h |
| Linezolid | Oxazolidinone | • Myelosuppression • optic neuropathy • serotonin syndrome with SSRIs | • CBC weekly if >10 d; pause serotonergic agents where possible |
| Corticosteroids (systemic) • prednisolone | Glucocorticoid | • Osteoporosis • hyperglycaemia • mood Δ • infection risk • adrenal suppression | • Consider bisphosphonate + Ca/VitD if ≥3 months |
| Methotrexate | Antimetabolite / DMARD | • Bone-marrow suppression • hepatotoxicity • pneumonitis | • Weekly dosing; folic acid 5 mg weekly; FBC/LFT/eGFR q1-3 m |
| Azathioprine | Purine analogue | • Leukopenia (TPMT deficiency) • pancreatitis | • Check TPMT or NUDT15 before start; CBC q1-3 m |
| Calcineurin inhibitors • cyclosporin, tacrolimus | Immunosuppressant | • Nephrotoxicity • hypertension • hyperkalaemia, neurotoxicity | • Trough levels; watch ACEi/ARB/NSAID combos |
| Biologic DMARDs • adalimumab | TNF-α inhibitor | • Reactivation TB/hepatitis • malignancy risk | • Screen TB, HBV, HCV before first dose |
| Lithium | Mood stabiliser | • Nephrogenic DI • hypothyroidism • ↑ levels with NSAID, ACEi, thiazide | • TFT/UEC/levels 3 monthly; counsel dehydration risk |
| Antipsychotics – atypical • olanzapine, quetiapine | Dopamine / 5-HT antagonists | • Metabolic syndrome • QT prolongation, NMS (rare) | • Baseline & annual lipids/BGL, weight, ECG |
| Typical antipsychotics • haloperidol | Dopamine antagonist | • EPS • tardive dyskinesia •hyperprolactinaemia • QT prolongation | • Procyclidine for acute dystonia; monitor prolactin |
| Metoclopramide | Antiemetic / D₂ blocker | • EPS • risk of NMS esp. with antipsychotics | • Limit to ≤5 d consecutive use |
| SSRIs • sertraline, escitalopram | Antidepressant | • GI upset • sexual dysfunction • hyponatraemia • ↑ bleed with NSAID, serotonin syndrome | • Elderly: check Na⁺ at 2-4 wk; add PPI if on chronic NSAID |
| SNRIs • venlafaxine | Antidepressant | • Hypertension (dose-dependent) • withdrawal if abrupt stop | • Check BP; taper slowly |
| MAOIs (non-selective) • phenelzine | Antidepressant | • Hypertensive crisis with tyramine • serotonin syndrome | • Avoid with SSRIs/SNRIs/meperidine/linezolid |
| TCAs • amitriptyline | Antidepressant | • Anticholinergic • QRS widening (overdose) • falls | • Avoid in elderly or severe CAD |
| Tramadol | Opioid + SNRI | • Seizure • serotonin syndrome • hypoglycaemia | • Reduce dose eGFR < 30; avoid with SSRIs/SNRIs |
| Strong opioids • oxycodone, fentanyl | µ-opioid agonist | • Constipation • respiratory depression • hyperalgesia, dependence | • Naloxone s/c + laxative co-prescribing in chronic therapy |
| Amiodarone | Class III anti-arrhythmic | • Thyroid (hyper + hypo) • pulmonary fibrosis • hepatitis • photosensitivity | • TFT/LFT/CXR baseline, at 6 & 12 mo then annually |
| Digoxin | Cardiac glycoside | • Bradyarrhythmia • digoxin toxicity ↑ with ↓K⁺ / ↓Mg²⁺ | • Target level 0.5–1 µg/L CHF; check 8 h post-dose |
| NOACs • apixaban, rivaroxaban | Direct factor Xa inhibitor | • Bleeding (GI > intracranial) • renal dosing • CYP3A4/P-gp substrates | • Dose-reduce apixaban if age ≥ 80, wt ≤ 60 kg, Cr ≥ 133 |
| Warfarin | Vitamin K antagonist | Bleeding • many drug/food interactions | • Target INR 2–3 (2.5–3.5 for mechanical AVR) |
| PDE-5 inhibitors • sildenafil | Vasodilator | • Hypotension with nitrates/GTN • visual ADR (NAION) | • Withhold GTN 24 h after sildenafil |
| Cisplatin | Alkylating chemotherapy | • Nephrotoxicity • ototoxicity • N/V | • Aggressive IV hydration; audiometry if tinnitus |
| Clozapine | Atypical antipsychotic | • Agranulocytosis • myocarditis • seizures | • Mandatory FBC: weekly × 18 wk → monthly |
| Variable “risk clusters” across classes | – | Drugs causing hyperkalaemia: ACEi ARB spironolactone trimethoprim, calcineurin inhibitor K⁺ supplements NSAIDs Drugs causing hyponatraemia (SIADH): SSRIs/SNRIs carbamazepine thiazides antipsychotics desmopressin Ototoxic drugs: Aminoglycosides loop diuretics cisplatin vancomycin | • Order EUC 3–5 d after adding another K⁺-raising agent • Check Na⁺ if delirium, seizure, or new falls • Baseline & post-therapy audiometry if |
“Triple whammy” = ACE inhibitor or ARB + diuretic + NSAID (including COX-2s)
- pathology
- ACEi/ARB: dilate efferent arteriole → ↓ intraglomerular pressure.
- Diuretic: ↓ circulating volume → ↓ renal perfusion.
- NSAID/COX-2: inhibit prostacyclin in afferent arteriole → vasoconstriction.
- ▶ Combined effect = precipitous fall in GFR → pre-renal AKI that may progress to intrinsic injury if prolonged.
- Each pair already raises acute kidney injury (AKI) risk; the full trio increases risk ≈30 % (NNH ≈ 158/yr in large cohort studies).
- NSAIDs also blunt the BP-lowering effect of ACEi/ARBs and antagonise diuretics → ↑ BP, fluid retention, heart-failure decompensation.
- Most cases are preventable by avoiding NSAIDs (including OTC ibuprofen, naproxen, diclofenac, celecoxib, meloxicam) in any patient already on an ACEi/ARB ± diuretic.
- Patient education:
- “Avoid Nurofen®, Advil®, Voltaren®, naproxen, celecoxib, meloxicam unless GP OKs it.”
- Provide sick-day rules card: hold ACEi/ARB, diuretic & NSAID if dehydrated (D&V, fever) and maintain hydration.
- Alternative analgesia: paracetamol ± topical NSAID, capsaicin, lidocaine patches; intra-articular steroid for flares; low-dose codeine or tramadol only if necessary.
- Pharmacy role: counsel against OTC NSAIDs, reinforce alternatives.
- Regular medicine reviews every ♻ 6–12 months (or earlier after hospital discharge).
If NSAID must be added (rare)
| Step | Rationale |
|---|---|
| Baseline weight, BP, S-Cr & electrolytes | Need “time-zero” value |
| Use lowest effective dose, shortest duration (≤ 3–5 days ideally) | Minimise cumulative risk |
| Re-check S-Cr, eGFR, K⁺ within 7–14 days (or sooner if frail) | Detect early AKI / hyperkalaemia |
| Reinforce fluid intake ≥ 2 L/day (unless HF) | Avoid hypovolaemia |
Recognising & managing triple-whammy AKI
Red flags: oliguria (< 0.5 mL kg⁻¹ h⁻¹), new lethargy, thirst, orthostatic hypotension, tachycardia, dry mucosae.
Diagnostic criteria (KDIGO):
- ↑ S-Cr ≥ 26.5 µmol/L in 48 h OR
- ≥ 1.5 × baseline within 7 d OR
- urine < 0.5 mL kg⁻¹ h⁻¹ for 6 h.
Immediate steps (primary care or ED):
- Stop NSAID (+ temporarily withhold ACEi/ARB, diuretic, metformin, SGLT2i, nephrotoxins).
- Oral or IV fluid resuscitation to euvolaemia.
- Monitor urine output & daily S-Cr.
Refer / phone renal or ED if:
- S-Cr > 3 × baseline or > 353 µmol/L
- eGFR < 30 mL/min
- anuria > 12 h
- refractory hyperkalaemia
- pulmonary oedema
- no improvement in 48–72 h.
After recovery
- Re-introduce ACEi/ARB cautiously; check S-Cr & K⁺ after 1–2 weeks.
- Never re-start NSAID in anyone with prior AKI.
- Adjust doses of renally cleared drugs to new baseline eGFR.
- Document episode & educate patient on future avoidance.